Treatment of emesis with morpholine tachykinin receptor antagonists

ABSTRACT

Substituted heterocycles of the structural formula: ##STR1## are tachykinin receptor antagonists useful in the treatment of inflammatory diseases, pain or migraine, asthma, emesis and nausea.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a division of application Ser. No. 08/206,771, filedMar. 4, 1994, abandoned.

SUMMARY OF THE INVENTION

This invention is concerned with novel compounds represented bystructural formula I: ##STR2## wherein R², R³, R⁶, R⁷, R⁸, R¹¹, R¹²,R¹³, A, B, p, Y and Z are hereinafter defined.

The invention is also concerned with pharmaceutical formulationscomprising these novel compounds as active ingredients and the use ofthe novel compounds and their formulations in the treatment of certaindisorders.

The compounds of this invention are tachykinin receptor antagonists andare useful in the treatment of inflammatory diseases, pain or migraine,asthma, emesis and nausea.

BACKGROUND OF THE INVENTION

Analgesia has historically been achieved in the central nervous systemby opiates and analogs which are addictive, and peripherally bycyclooxygenase inhibitors that have gastric side effects. Substance Pantagonists may induce analgesia both centrally and peripherally. Inaddition, substance P antagonists are inhibitory of neurogenicinflammation.

The neuropeptide receptors for substance P (neurokinin-1; NK-1) arewidely distributed throughout the mammalian nervous system (especiallybrain and spinal ganglia), the circulatory system and peripheral tissues(especially the duodenum and jejunum) and are involved in regulating anumber of diverse biological processes. This includes sensory perceptionof olfaction, vision, audition and pain, movement control, gastricmotility, vasodilation, salivation, and micturition (B. Pernow,Pharmacol. Rev., 1983, 35, 85-141 ). The NK1 and NK2 receptor subtypesare implicated in synaptic transmission (Laneuville et al., Life Sci.,42:1295-1305 (1988)).

The receptor for substance P is a member of the superfamily of Gprotein-coupled receptors. This superfamily is an extremely diversegroup of receptors in terms of activating ligands and biologicalfunctions. In addition to the tachykinin receptors, this receptorsuperfamily includes the opsins, the adrenergic receptors, themuscarinic receptors, the dopamine receptors, the serotonin receptors, athyroid-stimulating hormone receptor, a luteinizinghormone-choriogonadotropic hormone receptor, the product of the oncogeneras, the yeast mating factor receptors, a Dictyostelium cAMP receptor,and receptors for other hormones and neurotransmitters (see A.D.Hershey, et al., J. Biol. Chem., 1991,226, 4366-4373).

Substance P (also called "SP" herein) is a naturally occurringundecapeptide belonging to the tachykinin family of peptides, the latterbeing so-named because of their prompt contractile action onextravascular smooth muscle tissue. The tachykinins are distinguished bya conserved carboxyl-terminal sequence Phe-X-Gly-Leu-Met-NH₂.

In addition to SP the known mammalian tachykinins include neurokinin Aand neurokinin B. The current nomenclature designates the receptors forSP, neurokinin A, and neurokinin B as NK-1, NK-2, and NK-3,respectively.

More specifically, substance P is a pharmacologically-activeneuropeptide that is produced in mammals and possesses a characteristicamino acid sequence (Chang et al., Nature New Biol. 232, 86 (1971); D.F. Veber et al., U.S. Pat. No. 4,680,283).

Substance P acts as a vasodilator, a depressant, stimulates salivationand produces increased capillary permeability. It is also capable ofproducing both analgesia and hyperalgesia in animals, depending on doseand pain responsiveness of the animal (see R. C. A. Frederickson et al.,Science, 199, 1359 (1978); P. Oehme et al., Science, 208,305 (1980)) andplays a role in sensory transmission and pain perception (T. M. Jessell,Advan. Biochem. Psychopharmacol, 28, 189 (1981 )). For example,substance P is believed inter alia to be involved in theneurotransmission of pain sensations Otsuka et al, "Role of Substance Pas a Sensory Transmitter in Spinal Cord and Sympathetic Ganglia" in 1982Substance P in the Nervous System, Ciba Foundation Symposium 91, 13-34(published by Pitman) and Otsuka and Yanagisawa, "Does Substance P Actas a Pain Transmitter?" TIPS (December 1987) 8 506-510!. In particular,substance P has been shown to be involved in the transmission of pain inmigraine (see B. E. B. Sandberg et al., Journal of Medicinal Chemistry,25, 1009 (1982)), and in arthritis (Levine et al. Science, (1984) 226547-549). These peptides have also been implicated in gastrointestinal(GI) disorders and diseases of the GI tract, such as inflammatory boweldisease, ulcerative colitis and Crohn's disease, etc. (see Mantyh etal., Neuroscience, 25 (3), 817-37 (1988) and D. Regoli in "Trends inCluster Headache" Ed. F. Sicuteri et al., Elsevier ScientificPublishers, Amsterdam, 1987, pp. 85-95).

Substance P may play a role in a neurogenic mechanism for arthritis(Kidd et al., "A Neurogenic Mechanism for Symmetric Arthritis" in TheLancet, 11 Nov. 1989 and Gronblad et al., "Neuropeptides in Synovium ofPatients with Rheumatoid Arthritis and Osteoarthritis" in J. Rheumatol.(1988) 15(12) 1807-10). Therefore, substance P may be involved in theinflammatory response in diseases such as rheumatoid arthritis andosteoarthritis (O'Byme et al., in Arthritis and Rheumatism (1990) 331023-8).

Evidence for the usefulness of tachykinin receptor antagonists in pain,headache, especially migraine, Alzheimer's disease, multiple sclerosis,attenuation of morphine withdrawal, cardivascular changes, oedema, suchas oedema caused by thermal injury, chronic inflammatory diseases suchas rheumatoid arthritis, asthma/bronchial hyperreactivity and otherrespiratory diseases including allergic rhinitus, inflammatory diseasesof the gut including ulcerative colitis and Crohn's disease, ocularinjury and ocular inflammatory diseases, proliferativevitreoretinopathy, irritable bowel syndrome and disorders of bladderfunction including cystitis and bladder detruser hyperreflexia isreviewed in "Tachykinin Receptors and Tachykinin Receptor Antagonists,"C. A. Maggi, R. Patacchini, P. Rovero and A. Giachetti, J. Auton.Pharmacol, (1993) 13, 23-93. Neurokinin-1 receptor antagonists alone orin combination with bradykinin receptor antagonists may also be usefulin the prevention and treatment of inflammatory conditions in the lowerurinary tract, especially cystitis (Giuliani, et al., J. Urology, 150,1014-1017 (1993)). Other disease areas where tachykinin antagonists arebelieved to be useful are allergic conditions (Hamelet et al., Can. J.Pharmacol. Physiol. (1988) 66 1361-7), immunoregulation (Lotz et al.,Science (1988) 241 1218-21, Kimball et al., J. Immunol. (1988) 141 (10)3564-9 and A. Perianin, et al., Biochem. Biophys. Res Commun. 161, 520(1989)) vasodilation, bronchospasm, reflex or neuronal control of theviscera (Mantyh et al., PNAS (1988) 85 3235-9) and, possibly byarresting or slowing β-amyloid-mediated neurodegenerative changes(Yankner et al., Science, (1990) 250, 279-82) in senile dementia of theAlzheimer type, Alzheimer's disease and Downs Syndrome. Substance P mayalso play a role in demyelinating diseases such as multiple sclerosisand amyotrophic lateral sclerosis J. Luber-Narod et. al., posterpresented at C.I.N.P. XVIIIth Congress, 28th Jun.-2nd Jul., 1992, inpress!. Antagonists selective for the neurokinin-I (NK-1) and/or theneurokinin-2 (NK-2) receptor may be useful in the treatment of asthmaticdisease (Frossard et al., Life Sci., 49, 1941-1953 (1991); Advenier, etal., Biochem. Biophys. Res. Comm., 184(3), 1418-1424 (1992)). Tachykininantagonists may also be useful in the treatment of small cellcarcinomas, in particular small cell lung cancer (SCLC) (Langdon et al.,Cancer Research (1992) 52, 4554-7).

It has furthermore been suggested that tachykinins have utility in thefollowing disorders: depression, dysthymic disorders, chronicobstructive airways disease, hypersensitivity disorders such as poisonivy, vasospastic diseases such as angina and Reynauld's disease,fibrosing and collagen diseases such as scleroderma and eosinophillicfascioliasis, reflex sympathetic dystrophy such as shoulder/handsyndrome, addiction disorders such as alcoholism, stress related somaticdisorders, neuropathy, neuralgia, disorder related to immune enhancementor suppression such as systemic lupus erythmatosis (EPO Publication No.0,436,334) conjunctivitis, vernal conjunctivitis, contact dermatitis,atropic dermatitis, urticaria, and other eczematoid dermatitis (EPOPublication No. 0,394,989) and emesis or nausea (Trends Pharmacol. Sci.,9, 334-341 (1988); Eur. J. Pharmacol., 249, R3-R4 (1993)).

Substance P antagonists may be useful in mediating neurogenic mucussecretion in mammalian airways and hence provide treatment andsymptomatic relief in diseases characterized by mucus secretion, inparticular, cystic fibrosis S. Ramname, et al., abstract presented at1993 ALA/ATS Int'l Conference, 16-19 May, 1993, published in Am. Rev. ofRespiratory Dis., May 1993, in press!.

In the recent past, some attempts have been made to provide peptide-likesubstances that are antagonists for substance P and other tachykininpeptides in order to more effectively treat the various disorders anddiseases listed above. See for example Lowe, Drugs of the Future, 17(12) 1115-1121 (1992) and European patent applications (EPO PublicationNos. 0,347,802, 0,401,177 and 0,412,452) which disclose various peptidesas neurokinin A antagonists. Also, PCT Patent Publication WO 93/14113discloses certain peptides as tachykinin antagonists. In addition, EPOPublication No. 0,336,230 discloses heptapeptides which are substance Pantagonists useful in the treatment of asthma. Merck U.S. Pat. No.4,680,283 also discloses peptidal analogs of substance P.

Certain inhibitors of tachykinins have been described in U.S. Pat. No.4,501,733, by replacing residues in substance P sequence by Trpresidues.

A further class of tachykinin receptor antagonists, comprising amonomeric or dimeric hexa- or heptapeptide unit in linear or cyclicform, is described in GB-A-2216529.

The peptide-like nature of such substances make them too labile from ametabolic point of view to serve as practical therapeutic agents in thetreatment of disease. The non-peptidic antagonists of the presentinvention, on the other hand, do not possess this drawback, as they areexpected to be more stable from a metabolic point of view than thepreviously-discussed agents.

It is known in the art that baclofen(β-(aminoethyl)-4-chlorobenzenepropanoic acid) in the central nervoussystem effectively blocks the excitatory activity of substance P, butbecause in many areas the excitatory responses to other compounds suchas acetylcholine and glutamate are inhibited as well, baclofen is notconsidered a specific substance P antagonist. Pfizer WIPO patentapplications (PCT Publication Nos. WO 90/05525, WO 90/05729, WO91/18899, WO 92/12151 and WO 92/12152) and publications (Science, 251,435-437 (1991); Science, 251, 437-439 (1991); J. Med. Chem.,35,2591-2600 (1992)) disclose 2-arylmethyl-3-substitutedamino-quinuclidine derivatives which are disclosed as being useful assubstance P antagonists for treating gastrointestinal disorders, centralnervous system disorders, inflammatory diseases and pain or migraine. AGlaxo European patent application (EPO Publication No. 0,360,390)discloses various spirolactam-substituted amino acids and peptides whichare antagonists or agonists of substance P. A Pfizer WIPO patentapplication (PCT Publication No. WO 92/06079) discloses fused-ringanalogs of nitrogen-containing nonaromatic heterocycles as useful forthe treatment of diseases mediated by an excess of substance P. A PfizerWIPO patent application (PCT Publication NO. WO 92/15585 discloses1-azabicyclo 3.2.2!nonan-3-amine derivatives as substance P antagonists.A Pfizer WIPO patent application (PCT Publication No. WO 93/10073)discloses ethylenediamine derivatives as substance P antagonists. PCTPublication No. WO 93/01169 discloses certain aromatic compounds astachykinin receptor antagonists. A Sanoff publication (Life Sci., 50,PL101-PL106 (1992)) discloses a 4-phenyl piperidine derivative as anantagonist of the neurokinin A (NK2) receptor.

Howson et al. (Biorg. & Med. Chem. Lett., 2 (6), 559-564 (1992))disclose certain 3-amino and 3-oxy quinnuclidine compounds and theirbinding to substance P receptors. EPO Publication 0,499,313 disclosescertain 3-oxy and 3-thio azabicyclic compounds as tachykininantagonists. U.S. Pat. No. 3,506,673 discloses certain 3-hydroxyquinuclidine compounds as central nervous system stimulants. A PfizerEPO Patent application (EPO Publication 0,436,334) discloses certain3-aminopiperidine compounds as substance P antagonists. U.S. Pat. No.5,064,838 discloses certain 1,4-disubstituted piperidinyl compounds asanalgesics. PCT Publication No. WO 92/12128 discloses certain piperidineand pyrrolidine compounds as analgesics. Peyronel, et al. (Biorg & Med.Chem. Lett., 2 (1), 37-40 (1992)) disclose a fused ring pyrrolidinecompound as a substance P antagonist. EPO Publication No. 0,360,390discloses certain spirolactam derivatives as substance P antagonists.U.S. Pat. No. 4,804,661 discloses certain piperazine compounds asanalgesics. U.S. Pat. No. 4,943,578 discloses certain piperazinecompounds useful in the treatment of pain. PCT Publication No. WO92/01679 discloses certain 1,4-disubstituted piperazines useful in thetreatment of mental disorders in which a dopaminergic deficit isimplicated. EPO Publication No. 0,577,394 discloses certain morpholineand thiomorpholine substance P antagonists, some of which are the parentcompounds to the instant prodrugs.

Prodrugs are entities structurally related to a biologically activesubstance (the "parent drug") which, after administration, release theparent drug in vivo as the result of some metabolic process, such asenzymatic or chemical hydrolysis of a carboxylic, phosphoric or sulfateester or reduction or oxidation of a susceptible functionality (see, forexample, discussions by (1) A. A. Sinkula and S. H. Yalkowsky, J. Pharm.Sci, 64, 181 (1975); (2) L. A. Svensson, Pharm Weekbl, 122, 245-250(1987); (3) L. P. Balant, E. Doelker and P. Buri Eur. J. Drug Metab. andPharmacokinetics, 15, 143-153 (1990); (4) N. Bodor, Drugs of the Future,6, 165-182 (1981); (5) Design of Biopharmaceutical Properties throughProdrugs and Analogs., E. B. Roche, Ed., American PharmaceuticalAssociation Academy of Pharmaceutical Sciences, Washington, DC, (1977);(6) H. Bundgaard Advanced Drug Delivery Reviews, 3, 39-65 (1989)). Theadvantage of a prodrug may lie in its physical properties, such asenhanced water solubility for parenteral administration compared to theparent drug, or it may enhance absorption from the digestive tract, orit may enhance drug stability for long-term storage. In general, aprodrug possesses less biological activity than its parent drug.

DETAILED DESCRIPTION OF THE INVENTION

The novel compounds of this invention are represented by structuralformula I: ##STR3## or a pharmaceutically acceptable salt thereof,wherein: R² and R³ are independently selected from the group consistingof:

(1) hydrogen,

(2) C₁₋₆ alkyl, unsubstituted or substituted with one or more of thesubstituents selected from:

(a) hydroxy,

(b) oxo,

(c) C₁₋₆ alkoxy,

(d) phenyl-C₁₋₃ alkoxy,

(e) phenyl,

(f) --CN,

(g) halo,

(h) --NR⁹ R¹⁰, wherein R⁹ and R¹⁰ are independently selected from:

(i) hydrogen,

(ii) C₁₋₆ alkyl,

(iii) hydroxy-C₁₋₆ alkyl, and

(iv) phenyl,

(i) --NR⁹ COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(j) --NR⁹ CO₂ R¹⁰, wherein R⁹ and R¹⁰ are as defined above.

(k) --CONR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(l) --COR⁹, wherein R⁹ is as defined above, and

(m) --CO₂ R⁹, wherein R⁹ is as defined above;

(3) C₂₋₆ alkenyl, unsubstituted or substituted with one or more of thesubstituent(s) selected from:

(a) hydroxy,

(b) oxo,

(c) C₁₋₆ alkoxy,

(d) phenyl-C₁₋₃ alkoxy,

(e) phenyl,

(f) --CN,

(g) halo,

(h) --CONR⁹ R¹⁰ wherein R⁹ and R¹⁰ are as defined above,

(i) --COR⁹ wherein R⁹ is as defined above,

(j) --CO₂ R⁹, wherein R⁹ is as defined above;

(4) C₂₋₆ alkynyl;

(5) phenyl, unsubstituted or substituted with one or more of thesubstituent(s) selected from:

(a) hydroxy,

(b) C₁₋₆ alkoxy,

(c) C₁₋₆ alkyl,

(d) C₂₋₅ alkenyl,

(e) halo,

(f) --CN,

(g) --NO₂,

(h) --CF₃,

(i) --(CH₂)_(m) --NR⁹ R¹⁰, wherein m, R⁹ and R¹⁰ are as defined above,

(j) --NR⁹ COR¹⁰, wherein R⁹ and R¹⁰ are as defined above.

(k) --NR⁹ CO₂ R¹⁰, wherein R⁹ and R¹⁰ are as defined above.

(l) --CONR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above.

(m) --CO₂ NR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above.

(n) --COR⁹, wherein R⁹ is as defined above;

(o) --CO₂ R⁹, wherein R⁹ is as defined above;

and the groups R² and R³ may be joined together to form a carbocyclicring selected from the group consisting of:

(a) cyclopentyl,

(b) cyclohexyl,

(c) phenyl,

and wherein the carbocyclic ring is unsubstituted or substituted withone or more substituents selected from:

(i) C₁₋₆ alkyl,

(ii) C₁₋₆ alkoxy,

(iii) --NR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(iv) halo, and

(v) trifluoromethyl;

and the groups R² and R³ may be joined together to form a heterocyclicring selected from the group consisting of:

(a) pyrrolidinyl,

(b) piperidinyl,

(c) pyrrolyl,

(d) pyridinyl,

(e) imidazolyl,

(f) furanyl,

(g) oxazolyl,

(h) thienyl, and

(i) thiazolyl,

and wherein the heterocyclic ting is unsubstituted or substituted withone or more substituent(s) selected from:

(i) C₁₋₆ alkyl,

(ii) oxo,

(iii) C₁₋₆ alkoxy,

(iv) --NR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(v) halo, and

(vi) trifluoromethyl;

R⁶, R⁷ and R⁸ are independently selected from the group consisting of:

(1) hydrogen;

(2) C₁₋₆ alkyl, unsubstituted or substituted with one or more of thesubstituents selected from:

(a) hydroxy,

(b) oxo,

(c) C₁₋₆ alkoxy,

(d) phenyl-C₁₋₃ alkoxy,

(e) phenyl,

(f) --CN,

(g) halo,

(h) --NR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(i) --NR⁹ COR¹⁰, wherein R⁹ and R¹⁰ are as defined above.

(j) --NR⁹ CO₂ R¹⁰, wherein R⁹ and R¹⁰ are as defined above.

(k) --CONR⁹ R₁₀, wherein R⁹ and R¹⁰ are as defined above.

(l) --COR⁹, wherein R⁹ is as defined above, and

(m) --CO2R⁹, wherein R⁹ is as defined above;

(3) C₂₋₆ alkenyl, unsubstituted or substituted with one or more of thesubstituent(s) selected from:

(a) hydroxy,

(b) oxo,

(c) C₁₋₆ alkoxy,

(d) phenyl-C₁₋₃ alkoxy,

(e) phenyl,

(f) --CN,

(g) halo,

(h) --CONR⁹ R¹⁰ wherein R⁹ and R¹⁰ are as defined above,

(i) --COR⁹ wherein R⁹ is as defined above,

(j) --CO₂ R⁹, wherein R⁹ is as defined above;

(4) C₂₋₆ alkynyl;

(5) phenyl, unsubstituted or substituted with one or more of thesubstituent(s) selected from:

(a) hydroxy,

(b) C₁₋₆ alkoxy,

(c) C₁₋₆ alkyl,

(d) C₂₋₅ alkenyl,

(e) halo,

(f) --CN,

(g) --NO₂,

(h) --CF₃,

(i) --(CH₂)_(m) --NR⁹ R¹⁰, wherein m, R⁹ and R¹⁰ are as defined above,

(j) --NR⁹ COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(k) --NR⁹ CO₂ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(l) --CONR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(m) --CO₂ NR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(n) --COR⁹, wherein R⁹ is as defined above;

(o) --CO₂ R⁹, wherein R⁹ is as defined above;

(6) halo,

(7) --CN,

(8) --CF₃,

(9) --NO₂,

(10) --SR¹⁴, wherein R¹⁴ is hydrogen or C₁₋₅ alkyl,

(11) --SOR¹⁴, wherein R¹⁴ is as defined above,

(12) --SO₂ R¹⁴, wherein R₁₄ is as defined above,

(13) NR⁹ COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(14) CONR⁹ COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(15) NR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(16) NR⁹ CO₂ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(17) hydroxy,

(18) C₁₋₆ alkoxy,

(19) COR⁹, wherein R⁹ is as defined above,

(20) CO₂ R⁹, wherein R⁹ is as defined above,

(21) 2-pyridyl,

(22) 3-pyridyl,

(23) 4-pyridyl,

(24) 5-tetrazolyl,

(25) 2-oxazolyl, and

(26) 2-thiazolyl;

R¹¹, R¹² and R¹³ are independently selected from the definitions of R⁶,R⁷ and R⁸, or --OX;

A is selected from the group consisting of:

(1) C₁₋₆ alkyl, unsubstituted or substituted with one or more of thesubstituents selected from:

(a) hydroxy,

(b) oxo,

(c) C₁₋₆ alkoxy,

(d) phenyl-C₁₋₃ alkoxy,

(e) phenyl,

(f) --CN,

(g) halo, wherein halo is fluoro, chloro, bromo or iodo,

(h) --NR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(i) --NR 9COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(j) --NR⁹ CO₂ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(k) --CONR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(l) --COR⁹, wherein R⁹ is as defined above, and

(m) --CO₂ R⁹, wherein R⁹ is as defined above;

(2) C₂₋₆ alkenyl, unsubstituted or substituted with one or more of thesubstituent(s) selected from:

(a) hydroxy,

(b) oxo,

(c) C₁₋₆ alkoxy,

(d) phenyl-C₁₋₃ alkoxy,

(e) phenyl,

(f) --CN,

(g) halo,

(h) --CONR⁹ R¹⁰ wherein R⁹ and R¹⁰ are as defined above,

(i) --COR⁹ wherein R⁹ is as defined above, and

(j) --CO₂ R⁹, wherein R⁹ is as defined above; and

(3) C₂₋₆ alkynyl;

B is a heterocycle, wherein the heterocycle is selected from the groupconsisting of: ##STR4## and wherein the heterocycle may be substitutedin addition to --X with one or more substituent(s) selected from:

(i) C₁₋₆ alkyl, unsubstituted or substituted with halo, --CF₃, --OCH₃,or phenyl,

(ii) C₁₋₆ alkoxy,

(iii) oxo,

(iv) hydroxy,

(v) thioxo,

(vi) --SR⁹, wherein R⁹ is as defined above,

(vii) halo,

(viii) cyano,

(ix) phenyl,

(x) trifluoromethyl,

(xi) --(CH₂)_(m) --NR⁹ R¹⁰, wherein m is 0, 1 or 2. and R⁹ and R¹⁰ areas defined above,

(xii) --NR⁹ COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(xiii) --CONR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(xiv) --CO₂ R⁹, wherein R⁹ is as defined above, and

(xv) --(CH₂)_(m) --OR⁹, wherein m and R⁹ are as defined above;

p is 0 or 1;

X is selected from:

(a) --PO(OH)O--•M⁺, wherein M⁺ is a pharmaceutically acceptablemonovalent counterion,

(b) --PO(O⁻)₂ •2M⁺,

(c) --PO(O⁻)₂ •2D²⁺, wherein D²⁺ is a pharmaceutically acceptabledivalent counterion,

(d) --CH(R⁴)--PO(OH)O⁻ •M⁺, wherein R⁴ is hydrogen or C₁₋₃ alkyl,

(e) --CH(R⁴)--PO(O⁻)₂ •2M⁺,

(f) --CH(R⁴)--PO(O⁻)₂ •D²⁺,

(g) --SO₃ ⁻ •M³⁰ ,

(h) --CH(R₄)--SO₃ ⁻ •M⁺,

(i) --CO--CH₂ CH₂ --CO₂ ⁻ •M⁺,

(j) --CH(CH₃)--O--CO--R⁵, wherein R⁵ is selected from the groupconsisting of: ##STR5## (k) hydrogen, with the proviso that if p is 0and none of R¹¹, R¹² or R¹³ are --OX, then X is other than hydrogen;

Y is selected from the group consisting of:

(1) a single bond,

(2) --O--,

(3) --S--,

(4) --CO--,

(5) --CH₂ --,

(6) --CHR₁₅ --, and

(7) --CR¹⁵ R¹⁶ --, wherein R¹⁵ and R¹⁶ are independently selected fromthe group consisting of:

(a) C₁₋₆ alkyl, unsubstituted or substituted with one or more of thesubstituents selected from:

(i) hydroxy,

(ii) oxo,

(iii) C₁₋₆ alkoxy,

(iv) phenyl-C₁₋₃ alkoxy,

(v) phenyl,

(vi) --CN,

(vii) halo,

(viii) --NR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(ix) --NR⁹ COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(x) --NR⁹ CO₂ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(xi) --CONR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(xii) --COR⁹, wherein R⁹ is as defined above, and

(xiii) --CO₂ R⁹, wherein R⁹ is as defined above;

(b) phenyl, unsubstituted or substituted with one or more of thesubstituent(s) selected from:

(i) hydroxy,

(ii) C₁₋₆ alkoxy,

(iii) C₁₋₆ alkyl,

(iv) C₂₋₅ alkenyl,

(v) halo,

(vi) --CN,

(vii) --NO₂,

(viii) --CF₃,

(ix) --(CH₂)_(m) --NR⁹ R¹⁰, wherein m, R⁹ and R¹⁰ are as defined above,

(x) --NR⁹ COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(xi) --NR⁹ CO₂ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(xii) --CONR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(xiii) --CO₂ NR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

(xiv) --COR⁹, wherein R⁹ is as defined above, and

(xv) --CO₂ R⁹, wherein R⁹ is as defined above;

Z is selected from:

(1) hydrogen,

(2) C₁₋₆ alkyl, and

(3) hydroxy, with the proviso that if Y is --O--, Z is other thanhydroxy, or if Y is --CHR¹⁵ --, then Z and R¹⁵ may be joined together toform a double bond.

The instant compounds are prodrugs of their parent compounds. Aprincipal advantage of the instant compounds is that they possessenhanced solubility in aqueous solutions relative to their parentcompounds. In addition, the prodrugs generally have diminished activityat antagonizing tachykinin receptors than their parent compounds. Thus,the activity exhibited upon administration of the prodrug is principallydue to the presence of the parent compound that results from cleavage ofthe prodrug.

The term "prodrug" refers to compounds which are drug precursors which,following administration and absorption, release the drug in vivo viasome metabolic process.

Prodrugs are entities structurally related to an biologically activesubstance (the "parent drug") which, after administration, release theparent drug in vivo as the result of some metabolic process, such asenzymatic or chemical hydrolysis of a carboxylic, phosphoric or sulfateester or reduction or oxidation of a susceptible functionality (see, forexample, discussions by (1) A. A. Sinkula and S. H. Yalkowsky, J. Pharm.Sci, 64, 181 (1975); (2) L. A. Svensson, Pharm Weekbl, 122, 245-250(1987); (3) L. P. Balant, E. Doelker and P. Buri Eur. J. Drug Metab. andPharmacokinetics, 15, 143-153 (1990); (4) N. Bodor, Drugs of the Future,6, 165-182 (1981); (5) Design of Biopharmaceutical Properties throughProdrugs and Analogs,, E. B. Roche, Ed., American PharmaceuticalAssociation Academy of Pharmaceutical Sciences, Washington, DC, (1977);(6) H. Bundgaard Advanced Drug Delivery Reviews, 3, 39-65 (1989)). Theadvantage of a prodrug may lie in its physical properties, such asenhanced water solubility for parenteral administration compared to theparent drug, or it may enhance absorption from the digestive tract, orit may enhance drug stability for long-term storage. In general, aprodrug possesses less biological activity than its parent drug. Aprodrug may also improve overall drug efficacy, for example, through thereduction of toxicity and unwanted effects of a drug by controlling itsabsorption, blood levels, metabolic distribution and cellular uptake.

The term "parent compound" or "parent drug" refers to the biologicallyactive entity that is released via enzymatic action of a metabolic or acatabolic process, or via a chemical process following administration ofthe prodrug. The parent compound may also be the starting material forthe preparation of its corresponding prodrug.

While all of the usual routes of administration are useful with thepresent compounds, the preferred routes of administration are oral andintravenous. After gastrointestinal absorption or intravenousadministration, the present compounds are hydrolyzed or otherwisecleaved in vivo to the corresponding parent compounds of formula I,wherein X is hydrogen or X is absent, or a salt thereof. Since theparent compounds may be relatively insoluble in aqueous solutions, theinstant prodrugs provide a distinct advantage by virtue of theirrelatively enhanced aqueous solubility.

The compounds of the present invention have asymmetric centers and thisinvention includes all of the optical isomers and mixtures thereof.

In addition compounds with carbon-carbon double bonds may occur in Z-and E- forms with all isomeric forms of the compounds being included inthe present invention.

When any variable (e.g., alkyl, aryl, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹²,R¹³, etc.) occurs more than one time in any variable or in Formula I,its definition on each ocurrence is independent of its definition atevery other occurrence.

As used herein, the term "alkyl" includes those alkyl groups of adesignated number of carbon atoms of either a straight, branched, orcyclic configuration. Examples of "alkyl" include methyl, ethyl, propyl,isopropyl, butyl, iso- sec- and ten-butyl, pentyl, hexyl, heptyl,3-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, norbomyl, and the like. "Alkoxy" represents an alkyl groupof indicated number of carbon atoms attached through an oxygen bridge,such as methoxy, ethoxy, propoxy, butoxy and pentoxy. "Alkenyl" isintended to include hydrocarbon chains of a specified number of carbonatoms of either a straight- or branched- configuration and at least oneunsaturation, which may occur at any point along the chain, such asethenyl, propenyl, butenyl, pentenyl, dimethylpentyl, and the like, andincludes E and Z forms, where applicable. "Halogen" or "halo", as usedherein, means fluoro, chloro, bromo and iodo.

The compounds of the present invention are capable of forming salts withvarious inorganic and organic acids and bases and such salts are alsowithin the scope of this invention. Examples of such acid addition salts(which are negative counterions defined herein as "M-") include acetate,adipate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, citrate, ethanesulfonate, fumarate, hemisulfate,2-hydroxyethylsulfonate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, lactate, malate, maleate, methanesulfonate,2-naphthalenesulfonate, oxalate, pamoate, persulfate, picrate, pivalate,propionate, salicylate, stearate, succinate, sulfate, tartrate, tosylate(p-toluenesulfonate), and undecanoate. Base salts (which arepharmaceutically acceptable monovalent cations defined herein as "M⁺ "or pharmaceutically acceptable divalent cations defined herein as "D²⁺", if appropriate) include ammonium salts, alkali metal salts such assodium, lithium and potassium salts, alkaline earth metal salts such asaluminum, calcium and magnesium salts, salts with organic bases such asdicyclohexylamine salts, N-methyl-D-glucamine, and salts with aminoacids such as arginine, lysine, omithine, and so forth. If M⁺ is amonovalent cation, it is recognized that if the definition 2M⁺ ispresent, each of M⁺ may be the same or different. In addition, it issimilarly recognized that if the definition 2M⁺ is present, a divalentcation D²⁺ may instead be present. Also, the basic nitrogen-containinggroups may be quaternized with such agents as: lower alkyl halides, suchas methyl, ethyl, propyl, and butyl chloride, bromides and iodides;dialkyl sulfates like dimethyl, diethyl, dibutyl; diamyl sulfates; longchain halides such as decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides; aralkyl halides like benzyl bromide and others.The non-toxic physiologically acceptable salts are preferred, althoughother salts are also useful, such as in isolating or purifying theproduct.

The salts may be formed by conventional means, such as by reacting thefree base form of the product with one or more equivalents of theappropriate acid in a solvent or medium in which the salt is insoluble,or in a solvent such as water which is removed in vacuo or by freezedrying or by exchanging the anions of an existing salt for another anionon a suitable ion exchange resin.

In the compounds of formula I it is preferred that:

R² and R³ are independently selected from the group consisting of:

(1 ) hydrogen,

(2) C₁₋₆ alkyl,

(3) C₂₋₆ alkenyl, and

(4) phenyl;

R⁶, R⁷ and R⁸ are independently selected from the group consisting of:

(1) hydrogen,

(2) C₁₋₆ alkyl,

(3) fluoro,

(4) chloro,

(5) bromo,

(6) iodo, and

(7) --CF₃ ;

R¹¹, R¹² and R¹³ are independently selected from the group consistingof:

(1) fluoro,

(2) chloro,

(3 ) bromo, and

(4) iodo;

A is unsubstituted C₁₋₆ alkyl;

B is selected from the group consisting of: ##STR6## p is 0; X isselected from:

(a) --PO(OH)O⁻ •M⁺, wherein M⁺ is a pharmaceutically acceptablemonovalent counterion,

(b) --PO(O⁻)₂ •2M⁺,

(c) --PO(O⁻)₂ •D²⁺, wherein D²⁺ is a pharmaceutically acceptabledivalent counterion,

(d) --CH(R⁴)--PO(OH)O⁻ •M⁺, wherein R⁴ is hydrogen or methyl,

(e) --CH(R⁴)--PO(O⁻)₂ •2M⁺, wherein R⁴ is hydrogen or methyl,

(f) --CH(R⁴)--PO(O⁻)₂ •D²⁺, wherein R⁴ is hydrogen or methyl,

(i) --CO--CH₂ CH₂ --CO₂ ⁻ •M⁺,

(j) --CH(CH₃)--O--CO--R⁵, wherein R⁵ is selected from the groupconsisting of: ##STR7## Y is --O--; Z is hydrogen or C₁₋₄ alkyl.

In the compounds of the present invention a preferred embodimentincludes those compounds wherein Z is C₁₋₄ alkyl. An especiallypreferred embodiment of the compounds of formula I includes thosecompounds wherein Z is --CH₃. These compounds bearing a substituent onthe alpha-carbon atom exibit advantageous pharmacological properties, inparticular, enhanced duration of action in models of extravasation,presumably due to biological stability and resistance to enzymaticdegradation.

In the compounds of the present invention if p is 1, it is preferredthat X is hydrogen or is absent.

In the compounds of the present invention a particularly preferredembodiment is that in which A is --CH₂ -- or --CH(CH₃)--.

A particularly preferred embodiment of the compounds of the presentinvention includes the prodrugs of compounds of formula I wherein --A--Bis a (1,2,4-triazolo)methyl or a (5-oxo-1,2,4-triazolo)methyl group.

Another particularly preferred embodiment of the compounds of thepresent invention includes the prodrugs of compounds of formula Iwherein --A--B is a (1,3-imidazolo)methyl or a(5-oxo-1,3-imidazolo)methyl group.

An additional particularly preferred embodiment of the compounds of thepresent invention includes those compounds of formula I wherein --A--Bis a (1,2,4-triazolo)methyl or a (5-oxo-1,2,4-triazolo)methyl groupbeating a phosphoryl group attached to the heterocycle.

Yet another particularly preferred embodiment of the compounds of thepresent invention includes those compounds of formula I wherein --A--Bis a (1,3-imidazolo)methyl or a (1,3-imidazolo)methyl group bearing aphosphoryl group attached to the heterocycle.

A preferred embodiment of the compounds of the present inventionincludes the compounds of formula I wherein X is selected from:

(a) --PO(O⁻)₂ •2M⁺, wherein M⁺ is a pharmaceutically acceptablemonovalent counterion,

(b) --PO(O⁻)₂ •D²⁺, wherein D²⁺ is a pharmaceutically acceptabledivalent counterion,

(c) --CH(CH₃)--O--CO--CH₂ CH₂ --NH₃ ⁺ •M⁻, and

(d) --CH(CH₃)--O--CO--CH₂ CH₂ --NH₂ ⁺ --(CH₂ CH₂ --OH)•M⁻.

In the compounds of the present invention a particularly preferredembodiment is that in which --A--B is selected from the following groupof substituents: ##STR8##

Specific compounds within the scope of the present invention include theprodrugs of the following parent compounds:

1) (±)-2-(3,5-bis(trifluoromethyl)benzyloxy)-3-phenyl-morpholine;

2) (2R,S)-(3,5-bis(trifluoromethyl)benzyloxy)-(3R)-phenyl-(6R)-methyl-morpholine;

3)(2R,S)-(3,5-bis(trifluoromethyl)benzyloxy)-(3S)-phenyl-(6R)-methyl-morpholine;

4)(±)-2-(3,5-bis(trifluoromethyl)benzyloxy)-3-phenyl-4-methylcarboxamido-morpholine;

5)(±)-2-(3,5-bis(trifluoromethyl)benzyloxy)-3-phenyl-4-methoxycarbonylmethyl-morpholine;

6)2-(2-(3,5-bis(trifluoromethyl)phenyl)ethenyl)-3-phenyl-5-oxo-morpholine;

7) 3-phenyl-2-(2-(3,5-bis (trifluoromethyl)phenyl)-ethyl)morpholine;

8)2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-6-(S)-methyl-morpholine;

9)2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(S)-methyl-morpholine;

10)2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-6-(S)-methyl-morpholine;

11)2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(S)-methyl-morpholine;

12)2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-5-(R)-methyl-morpholine;

13)2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(R)-methyl-morpholine;

14)2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-5-(R)-methyl-morpholine;

15)2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(R)-methyl-morpholine;

16) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-morpholine;

17)4-(3-(1,2,4-triazolo)methyl)-2-(S)-(3,5-bis(tri-fluoromethyl)benzyloxy)-3-(S)-phenyl-morpholine;

18) 4-(3-(5-oxo-1H ,4H-1,2,4-triazolo)methyl)-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-morpholine;

19)2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-6-(R)-methyl-morpholine;

20)2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-6-(R)-methyl-morpholine;

21)2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(R)-methyl-morpholine;

22)2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(R)-methyl-morpholine;

23)2-(R)-(3,5-bis(trifluoromethyl)-benzyloxy)-3-(S)-phenyl-5-(S)-methyl-morpholine;

24)2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(S)-methyl-morpholine;

25)2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-5-(S)-methyl-morpholine;

26)2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(R)-phenyl-morpholine;

27)2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(R)-phenyl-morpholine;

28)2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-5-(S)-phenyl-morpholine;

29)2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-5-(S)-phenyl-morpholine;

30)2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-6-(R)-methyl-3-(S)-phenyl-4-(3-(1,2,4-triazolo)methyl)-morpholine;

31)2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-6-(R)-methyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-3-(S)-phenyl-morpholine;

32) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-morpholine;

33)4-(3-(1,2,4-triazolo)methyl)-2-(S)-(3,5-bis(tri-fluoromethyl)benzyloxy)-3-(R)-phenyl-morpholine;

34) 4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-2-(S)-(3,5-bis-(trifluoromethyl)benzyloxy)-3-(R)-phenyl-morpholine;

35)4-(2-(imidazolo)methyl)-2-(S)-(3,5-bis(trifluoro-methyl)-benzyloxy)-3-(R)-phenyl-morpholine;

36)4-(4-(imidazolo)methyl)-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-morpholine;

37)4-(aminocarbonylmethyl)-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-morpholine;

38)4-(2-(imidazolo)methyl)-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-morpholine;

39)4-(4-(imidazolo)methyl)-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-morpholine;

40)4-(2-(imidazolo)methyl)-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(R)-methyl-morpholine;

41)4-(4-(imidazolo)methyl)-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6(R)-methyl-morpholine;

42)2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-((6-hydroxy)-hexyl)-3-(R)-phenyl-morpholine;

43)2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(5-(methylaminocarbonyl)pentyl)-3-(R)-phenyl-morpholine;

44)4-(3-(1,2,4-triazolo)methyl)-2-(3,5-dimethyl-benzyloxy)-3-phenyl-morpholine;

45)4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-2-(3,5-dimethyl)benzyloxy)-3-phenyl-morpholine;

46)4-(3-(1,2,4-triazolo)methyl)-2-(3,5-di(tert-butyl)-benzyloxy)-3-phenyl-morpholine;

47)4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-2-(3,5-di(tert-butyl)benzyloxy)-3-phenyl-morpholine;

48)4-(3-(1,2,4-triazolo)methyl)-2-(3-(tert-butyl)-5-methylbenzyloxy)-3-phenyl-morpholine;

49) 4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-2-(3-(tert-butyl)-5-methylbenzyloxy)-3-phenyl-morpholine;

50)4-(3-(1,2,4-triazolo)methyl)-2-(3-(trifluoro-methyl)-5-methylbenzyloxy)-3-phenyl-morpholine;

51) 4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-2-(3-(trifluoromethyl)-5-methylbenzyloxy)-3-phenyl-morpholine;

52)4-(3-(1,2,4-triazolo)methyl)-2-(3-(tert-butyl)-5-(trifluoromethyl)benzyloxy)-3-phenyl-morpholine;

53) 4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-2-(3-(tert-butyl)-5-(trifluoromethyl)benzyloxy)-3-phenyl-morpholine;

54)4-(2-(imidazolo)methyl)-2-(3,5-dimethyl-benzyloxy)-3-phenyl-morpholine;

55)4-(4-(imidazolo)methyl)-2-(3,5-dimethyl-benzyloxy)-3-phenyl-morpholine;

56)4-(2-(imidazolo)methyl)-2-(3,5-di(tert-butyl)-benzyloxy)-3-phenyl-morpholine;

57)4-(4-(imidazolo)methyl)-2-(3,5-di(tert-butyl)-benzyloxy)-3-phenyl-morpholine;

58)4-(2-(imidazolo)methyl)-2-(3-(tert-butyl)-5-methylbenzyloxy)-3-phenyl-morpholine;

59)4-(4-(imidazolo)methyl)-2-(3-(tert-butyl)-5-methylbenzyloxy)-3-phenyl-morpholine;

60)4-(2-(imidazolo)methyl)-2-(3-(trifluoro-methyl)-5-methylbenzyloxy)-3-phenyl-morpholine;

61)4-(4-(imidazolo)methyl)-2-(3-(trifluoro-methyl)-5-methylbenzyloxy)-3-phenyl-morpholine;

62)4-(2-(imidazolo)methyl)-2-(3-(tert-butyl)-5-(trifluoromethyl)benzyloxy)-3-phenyl-morpholine;

63) 2-(S)-(3,5-dichlorobenzyloxy)-3-(S)-phenyl-morpholine;

64)2-(S)-(3,5-dichlorobenzyloxy)-4-(3-(5-oxo-1,2,4-triazolo)methyl)-3-(S)-phenyl-morpholine;

65)2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(methoxycarbonylmethyl)-3-(S)-phenyl-morpholine;

66)2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(carboxymethyl)-3-(S)-phenyl-morpholine;

67)2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-((2-aminoethyl)aminocarbonylmethyl)-3-(S)-phenyl-morpholine;

68)2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-((3-aminopropyl)amino-carbonylmethyl)-3-(S)-phenyl-morpholine;

69) 4-benzyl-5-(S),6-(R)-dimethyl-3-(S)-phenylmorpholinone and4-benzyl-5-(R),6-(S)-dimethyl-3-(S)-phenyl-morpholinone;

70) 2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)- 5-(S),6-(R) or5-(R),6-(S)-dimethyl!-3-(S)-phenyl-morpholinone;

71) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)- 5-(R),6-(S) or5-(S),6-(R)-dimethyl!-3-(S)-phenyl-morpholinone;

72)2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(3-(1,2,4-triazolo)methyl)-5-(S),6-(R) or 5-(R),6-(S)-dimethyl!-3-(S)-phenyl-morpholinone;

73)2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(3-(5-oxo-1,2,4-triazolo)methyl)-5-(S),6-(R) or 5-(R),6-(S)-dimethyl!-3-(S)-phenyl-morpholinone;

74)2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(3-(1,2,4-triazolo)methyl)-5-(R),6-(S) or 5-(S),6-(R)-dimethyl!-3-(S)-phenylmorpholinone;

75)2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(3-(5-oxo-1,2,4-triazolo)methyl)-5o(R),6-(S) or 5-(S),6-(R)-dimethyl!-3-(S)-phenyl-morpholinone;

76)2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(2-(1-(4-benzyl)piperidino)ethyl)-3-(S)-phenyl-morpholine;

77) 3-(S)-(4-fluorophenyl)-4-benzyl-2-morpholinone;

78)2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-(4-fluorophenyl)-4-benzyl-morpholine;

79)2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-(4-fluorophenyl)morpholine:

80)2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl-morpholine;

81)2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-((3-pyridyl)methylcarbonyl)-3-(R)-phenyl-morpholine;

82)2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(methoxycarbonylpentyl)-3-(R)-phenyl-morpholine;

83)2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(carboxypentyl)-3-(R)-phenyl-morpholine;

84)2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(methylaminocarbonylpentyl)-6-oxo-hexyl)-3-(R)-phenyl-morpholine;

85)2-(R)-(3,5-bis(trifluoromethyl)benzoyloxy)-3-(S)-phenyl-4-benzyl-morpholine;

86)2-(R)-(1-(3,5-bis(trifluoromethyl)phenyl)ethenyloxy)-3-(S)-phenyl-4-benzyl-morpholine;

87)2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl-morpholine;

88)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl-morpholine;

89)2-(R)-(1-(S)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

90)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

91)2-(R)-(3,5-bis(trifluoromethyl)benzoyloxy)-3-(S)-(4-fluoro)phenyl-4-benzyl-morpholine;

92)2-(R)-(1-(3,5-bis(trifluoromethyl)phenyl)ethenyloxy)-3-(S)-(4-fluoro)phenyl-4-benzyl-morpholine;

93)2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-morpholine;

94)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-morpholine;

95)2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

96)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

97) 2-(R)-(1-(R)-(1-(3-(methyl)naphthyl))ethoxy)-3-(S)-phenyl-4-(3-(-1,2,4-triazolo)methyl-morpholine;

98)2-(R)-(1-(R)-(1-(3-(methyl)naphthyl))ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

99)2-(R)-(1-(R)-(3-(fluoro)-5-(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl-morpholine;

100)2-(R)-(1-(R)-(3-(fluoro)-5-(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

101)2-(R)-(1-(R)-(3-(chloro)-5-(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl-morpholine;

102)2-(R)-(1-(R)-(3-(chloro)-5-(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

103) 2-(R)-(1-(R)-(3,5-(dimethyl)phenyl)ethoxy)-3-(S)-phenyl-morpholine;

104)2-(R)-(1-(R)-(3,5-(dimethyl)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

105)2-(R)-(1-(R)-(3-(fluoro)-5-(methyl)phenyl)ethoxy)-3-(S)-phenyl-morpholine;

106)2-(R)-(1-(R)-(3-(fluoro)-5-(methyl)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

107)2-(R)-(1-(R)-(3-(chloro)-5-(methyl)phenyl)ethoxy)-3-(S)-phenyl-morpholine;

108)2-(R)-(1-(R)-(3-(chloro)-5-(methyl)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

109)2-(R)-(1-(R)-(3-(bromo)-5-(methyl)phenyl)ethoxy)-3-(S)-phenyl-morpholine;

110)2-(R)-(1-(R)-(3-(bromo)-5-(methyl)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

111) 2-(R)-(1-(R)-(3-(isopropoxy)phenyl)ethoxy)-3-(S)-phenyl-morpholine;

112)2-(R)-(1-(R)-(3-(isopropoxy)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

113)2-(R)-(1-(R)-(3-(isopropoxy)-5-trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl-morpholine;

114)2-(R)-(1-(R)-(3-(isopropoxy)-5-trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

115)2-(R)-(1-(R)-(3-(chloro)-5-(isopropoxy)phenyl)ethoxy)-3-(S)-phenyl-morpholine;

116)2-(R)-(1-(R)-(3-(chloro)-5-(isopropoxy)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

117)2-(R)-(1-(R)-(3-(fluoro)-5-(isopropoxy)phenyl)ethoxy)-3-(S)-phenyl-morpholine;

118)2-(R)-(1-(R)-(3-(fluoro)-5-(isopropoxy)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

119)2-(R)-(1-(R)-(1-(3-(trifluoromethyl)naphthyl))ethoxy)-3-(S)-phenyl-4-(3-(-1,2,4-triazolo)methyl-morpholine;

120)2-(R)-(1-(R)-(1-(3-(trifluoromethyl)naphthyl))ethoxy)-3-(S)-phenyl-4-(3-(2°oxo-1,3-imidazolo)methyl-morpholine;

121)2-(R)-(1-(R)-(3-(t-butyl)-5-(chloro)phenyl)ethoxy)-3-(S)-phenyl-morpholine;

122)2-(R)-(1-(R)-(3-(t-butyl)-5-(chloro)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

123)2-(R)-(1-(R)-(3-(t-butyl)-5-(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl-morpholine;

124)2-(R)-(1-(R)-(3-(t-butyl)-5-(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

125)2-(R)-(1-(R)-(3,5-(dimethyl)-4-(fluoro)phenyl)ethoxy)-3-(S)-phenyl-morpholine;

126)2-(R)-(1-(R)-(3,5-(dimethyl)-4-(fluoro)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

127)2-(R)-(1-(R)o(3,5-(dimethyl)-4-(chloro)phenyl)ethoxy)-3-(S)-phenyl-morpholine;

128)2-(R)-(1-(R)-(3,5-(dimethyl)-4-(chloro)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

129)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-4-(fluoro)phenyl)ethoxy)-3-(S)-phenyl-morpholine;

130)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-4-(fluoro)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

131 )2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-4-chloro)phenyl)ethoxy)-3-(S)-phenyl-morpholine;

132)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-4-chloro)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

133) 2-(R)-(1-(R)-(3,5-(dichloro)phenyl)ethoxy)-3-(S)-phenyl-morpholine;

134)2-(R)-(1-(R)-(3,5-(dichloro)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

135) 2-(R)-(1-(R)-(3,5-(difluoro)phenyl)ethoxy)-3-(S)-phenyl-morpholine;

136)2-(R)-(1-(R)-(3,5-(difluoro)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

137) 2-(R)-(1-(R)-(1-(naphthyl)ethoxy)-3-(S)-phenyl-morpholine;

138)2-(R)-(1-(R)-(1-(naphthyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

139)2-(R)-(1-(R)-(1-(4-(fluoro)naphthyl))ethoxy)-3-(S)-phenyl-morpholine;

140)2-(R)-(1-(R)-(1-(4-(fluoro)naphthyl))ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

141)2-(R)-(1-(R)-(1-(3-(fluoro)naphthyl))ethoxy)-3-(S)-phenyl-morpholine;

142)2-(R)-(1-(R)-(1-(3-(fluoro)naphthyl))ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

143)2-(R)-(1-(R)-(1-(3-(chloro)naphthyl))ethoxy)-3-(S)-phenyl-morpholine;

144)2-(R)-(1-(R)o(1-(3-(chloro)naphthyl))ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

145)2-(R)-(1-(R)-(1-(3-(methyl)naphthyl))ethoxy)-3-(S)-phenyl-morpholine;

146)2-(R)-(1-(R)-(1-(3-(methyl)naphthyl))ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

147)2-(R)-(1-(R)-(1-(3-(trifluoromethyl)naphthyl))ethoxy)-3-(S)-phenyl-morpholine;

148)2-(R)-(1-(R)-(1-(3-(trifluoromethyl)naphthyl))ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

149)2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-(4-hydroxy)phenyl-morpholine;

150)2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-(4-hydroxy)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

151)2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy-3-(S)-phenyl-morpholine;

152)2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)phenyl-morpholine;

153)2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl)phenylethoxy)-3-(S)-phenyl-morpholine;

154)2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-morpholine;

155)2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

156)2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

157)2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl)phenylethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

158)2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

159)2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

160)2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

161)2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl)phenylethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

162)2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

163)2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(4-(2-oxo-1,3-imidazolo)methyl-morpholine;

164) 164)2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(4-(2-oxo-1,3-imidazolo)methyl-morpholine;

165)2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl)phenylethoxy)-3-(S)-phenyl-4-(4-(2-oxo-1,3-imidazolo)methyl-morpholine;

166)2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(4-(2-oxo-1,3-imidazolo)methyl-morpholine;

167)2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(2-imidazolo)methyl-morpholine;

168)2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(2-imidazolo)methyl-morpholine;

169)2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl)phenylethoxy)-3-(S)-phenyl-4-(2-imidazolo)methyl-morpholine;

170)2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(2-imidazolo)methyl-morpholine;

171)2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(4-imidazolo)methyl-morpholine;

172)2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(4-imidazolo)methyl-morpholine;

173)2-(R)-(l-(R)-(2-fluoro-5-trifluoromethyl)phenylethoxy)-3-(S)-phenyl-4-(4-imidazolo)methyl-morpholine;

174)2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(4-imidazolo)methyl-morpholine;

175)2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(5-tetrazolo)methyl-morpholine;

176)2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(5-tetrazolo)methyl-morpholine;

177)2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl)phenylethoxy)-3-(S)-phenyl-4-(5-tetrazolo)methyl-morpholine;

178)2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(5-tetrazolo)methyl-morpholine;

179)2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(2-oxo-5H-pyrrol-4-yl)methyl-morpholine;

180)2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(2-oxo-5H-pyrrol-4-yl)methyl-morpholine;

181)2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl)phenylethoxy)-3-(S)-phenyl-4-(2-oxo-5H-pyrrol-4-yl)methyl-morpholine;

182)2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(2-oxo-5H-pyrrol-4-yl)methyl-morpholine;

183)2-(S)-(2-chloro-5-trifluoromethyl)benzyloxy-3-(S)-phenyl-morpholine;

184) 2-(S)-(2-chloro-5-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)phenyl-morpholine;

185)2-(R)-(1-(R)-(2-chloro-5-trifluoromethyl)phenylethoxy)-3-(S)-phenyl-morpholine;

186)2-(R)-(1-(R)-(2-chloro-5-trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-morpholine;

187)2-(S)-(2-chloro-5-trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

188)2-(S)-(2-chloro-5-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

189)2-(R)-(1-(R)-(2-chloro-5-trifluoromethyl)phenylethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

190)2-(R)-(1-(R)-(2-chloro-5-trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

191)2-(S)-(2-chloro-5-trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

192)2-(S)-(2-chloro-5-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

193)2-(R)-(1-(R)-(2-chloro-5-trifluoromethyl)phenylethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

194)2-(R)-(1-(R)-(2-chloro-5-trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

195)2-(S)-(2-chloro-5-trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(4-(2-oxo-1,3-imidazolo)methyl-morpholine;

196)2-(S)-(2-chloro-5-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(4-(2-oxo-1,3-imidazolo)methyl-morpholine;

197)2-(R)-(1-(R)-(2-chloro-5-trifluoromethyl)phenylethoxy)-3-(S)-phenyl-4-(4-(2-oxo-1,3-imidazolo)methyl-morpholine;

198)2-(R)-(1-(R)-(2-chloro-5-trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(4-(2-oxo-1,3-imidazolo)methyl-morpholine;

199)2-(S)-(2-chloro-5-trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(2imidazolo)methyl-morpholine;

200) 2-(S)-(2-chloro-5-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(2-imidazolo)methyl-morpholine;

201)2-(R)-(1-(R)-(2-chloro-5-trifluoromethyl)phenylethoxy)-3-(S)-phenyl-4-(2-imidazolo)methyl-morpholine;

202)2-(R)-(1-(R)-(2-chloro-5-trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(2-imidazolo)methyl-morpholine;

203)2-(S)-(2-chloro-5-trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(4-imidazolo)methyl-morpholine;

204)2-(S)-(2-chloro-5-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(4-imidazolo)methyl-morpholine;

205)2-(R)-(1-(R)-(2-chloro-5-trifluoromethyl)phenylethoxy)-3-(S)-phenyl-4-(4-imidazolo)methyl-morpholine;

206)2-(R)-(1-(R)-(2-chloro-5-trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(4-imidazolo)methyl-morpholine;

207) 2-(S)-(2-chloro-5-trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(5-tetrazolo)methyl-morpholine;

208) 2-(S)-(2-chloro-5-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(5-tetrazolo)methyl-morpholine;

209)2-(R)-(1-(R)-(2-chloro-5-trifluoromethyl)phenylethoxy)-3-(S)-phenyl-4-(5-tetrazolo)methyl-morpholine;

210)2-(R)-(1-(R)-(2-chloro-5-trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(5-tetrazolo)methyl-morpholine;

211)2-(S)-(2-chloro-5-trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(2-oxo-5H-pyrrol-4-yl)methyl-morpholine;

212) 2-(S)-(2-chloro-5-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(2-oxo-5H-pyrrol-4-yl)methyl-morpholine;

213)2-(R)-(1-(R)-(2-chloro-5-trifluoromethyl)phenylethoxy)-3-(S)-phenyl-4-(2-oxo-5H-pyrrol-4-yl)methyl-morpholine;

214)2-(R)-(1-(R)-(2--Chloro-5-trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(2-oxo-5H-pyrrol-4-yl)methyl-morpholine;

215) 2-(S)-(3-methyl)benzyloxy-3-(S)-phenyl-morpholine;

216) 2-(S)-(3-methyl)benzyloxy-3-(S)-(4-fluoro)phenyl-morpholine;

217) 2-(R)-(1-(R)-(3-methyl)phenylethoxy)-3-(S)-phenyl-morpholine;

218)2-(R)-(1-(R)-(3-methyl)phenylethoxy)o3-(S)-(4-fluoro)phenyl-morpholine;

219)2-(S)-(3-methyl)benzyloxy-3-(S)-phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

220)2-(S)-(3-methyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

221)2-(R)-(1-(R)-(3-methyl)phenylethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

222)2-(R)-(1-(R)-(3-methyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

223)2-(S)-(3-methyl)benzyloxy-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

224)2-(S)-(3-methyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

225)2-(R)-(1-(R)-(3-methyl)phenylethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

226)2-(R)-(1-(R)-(3-methyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

227)2-(S)-(3-methyl)benzyloxy-3-(S)-phenyl-4-(4-(2-oxo-1,3-imidazolo)methyl-morpholine;

228)2-(S)-(3-methyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(4-(2-oxo-1,3-imidazolo)methyl-morpholine;

229)2-(R)-(1-(R)-(3-methyl)phenylethoxy)-3-(S)-phenyl-4-(4-(2-oxo-1,3-imidazolo)methyl-morpholine;

230)2-(R)-(1-(R)-(3-methyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(4-(2-oxo-1,3-imidazolo)methyl-morpholine;

231)2-(S)-(3-methyl)benzyloxy-3-(S)-phenyl-4-(2-imidazolo)methylmorpholine;

232)2-(S)-(3-methyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(2-imidazolo)methyl-morpholine;

233)2-(R)-(1-(R)-(3-methyl)phenylethoxy)-3-(S)-phenyl-4-(2-imidazolo)methyl-morpholine;

234)2-(R)-(1-(R)-(3-methyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(2-imidazolo)methyl-morpholine;

235)2-(S)-(3-methyl)benzyloxy-3-(S)-phenyl-4-(4-imidazolo)methylmorpholine;

236)2-(S)-(3-methyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(4-imidazolo)methyl-morpholine;

237)2-(R)-(1-(R)-(3-methyl)phenylethoxy)-3-(S)-phenyl-4-(4-imidazolo)methyl-morpholine;

238)2-(R)-(1-(R)-(3-methyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(4-imidazolo)methyl-morpholine;

239)2-(S)-(3-methyl)benzyloxy-3-(S)-phenyl-4-(5-tetrazolo)methylmorpholine;

240)2-(S)-(3-methyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(5-tetrazolo)methyl-morpholine;

241)2-(R)-(1-(R)-(3-methyl)phenylethoxy)-3-(S)-phenyl-4-(5-tetrazolo)methyl-morpholine;

242)2-(R)-(1-(R)-(3-methyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(5-tetrazolo)methyl-morpholine;

243)2-(S)-(3-methyl)benzyloxy-3-(S)-phenyl-4-(2-oxo-5H-pyrrol-4-yl)methyl-morpholine;

244)2-(S)-(3-methyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(2-oxo-5H-pyrrol-4-yl)methyl-morpholine;

245)2-(R)-(1-(R)-(3-methyl)phenylethoxy)-3-(S)-phenyl-4-(2-oxo-5H-pyrrol-4-yl)methyl-morpholine;

246) 2-(R)-(1-(R)-(3-methyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(

247) 2-oxo-5H-pyrrol-4-yl)methyl-morpholine;2-(S)-(3-bromo)benzyloxy-3-(S)-phenyl-morpholine;

248) 2-(S)-(3-bromo)benzyloxy-3-(S)-(4-fluoro)phenyl-morpholine;

249) 2-(R)-(1-(R)-(3-bromo)phenylethoxy)-3-(S)-phenyl-morpholine;

250)2-(R)-(1-(R)-(3-bromo)phenylethoxy)-3-(S)-(4-fluoro)phenyl-morpholine;

251)2-(S)-(3-bromo)benzyloxy-3-(S)-phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

252)2-(S)-(3-bromo)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

253)2-(R)-(1-(R)-(3-bromo)phenylethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

254)2-(R)-(1-(R)-(3-bromo)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

255)2-(S)-(3-bromo)benzyloxy-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

256)2-(S)-(3-bromo)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

257)2-(R)-(1-(R)-(3-bromo)phenylethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

258)2-(R)-(l-(R)-(3-bromo)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

259)2-(S)-(3-bromo)benzyloxy-3-(S)-phenyl-4-(4-(2-oxo-1,3-imidazolo)methyl-morpholine;

260) 2-(S)-(3-bromo)benzyloxy-3-(S)-(4-fluoro)p he n yl-4-(4-(2-oxo-1,3-imidazolo)methyl-morpholine;

261)2-(R)-(1-(R)o(3-bromo)phenylethoxy)-3-(S)-phenyl-4-(4-(2-oxo-1,3-imidazolo)methyl-morpholine;

262)2-(R)-(1-(R)-(3-bromo)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(4-(2-oxo-1,3-imidazolo)methyl-morpholine;

263)2-(S)-(3-bromo)benzyloxy-3-(S)-phenyl-4-(2-imidazolo)methylmorpholine;

264)2-(S)-(3-bromo)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(2-imidazolo)methyl-morpholine;

265)2-(R)-(1-(R)-(3-bromo)phenylethoxy)-3-(S)-phenyl-4-(2-imidazolo)methyl-morpholine;

266)2-(R)-(1-(R)-(3-bromo)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(2-imidazolo)methyl-morpholine;

267)2-(S)-(3-bromo)benzyloxy-3-(S)-phenyl-4-(4-imidazolo)methyl-morpholine;

268)2-(S)-(3-bromo)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(4-imidazolo)methyl-morpholine;

269)2-(R)-(1-(R)-(3-bromo)phenylethoxy)-3-(S)-phenyl-4-(4-imidazolo)methyl-morpholine;

270)2-(R)-(1-(R)-(3-bromo)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(4-imidazolo)methyl-morpholine;

271)2-(S)-(3-bromo)benzyloxy-3-(S)-phenyl-4-(5-tetrazolo)methyl-morpholine;

272)2-(S)-(3-bromo)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(5-tetrazolo)methyl-morpholine;

273)2-(R)-(1-(R)-(3-bromo)phenylethoxy)-3-(S)-phenyl-4-(5-tetrazolo)methyl-morpholine;

274) 2-(R) -(1-(R)-(3-bromo)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(5-tetrazolo)methyl-morpholine;

275) 2-(S)-(3-bromo)benzyloxy-3-(S)-phenyl-4-(2-oxo-5H-pyrrol-4-yl)methyl-morpholine;

276)2-(S)-(3-bromo)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(2-oxo-5H-pyrrol-4-yl)methyl-morpholine;

277)2-(R)-(1-(R)-(3-bromo)phenylethoxy)-3-(S)-phenyl-4-(2-oxo-5H-pyrrol-4-yl)methyl-morpholine;

278)2-(R)-(1-(R)-(3-bromo)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(2-oxo-5H-pyrrol-4-yl)methyl-morpholine;

279) 2-(S)-(3-chloro)benzyloxy-3-(S)-phenyl-morpholine;

280) 2-(S)-(3-chloro)benzyloxy-3-(S)-(4-fluoro)phenyl-morpholine;

281) 2-(R)-(1-(R)-(3-chloro)phenylethoxy)-3-(S)-phenyl-morpholine;

282)2-(R)-(1-(R)-(3-chloro)phenylethoxy)-3-(S)-(4-fluoro)phenyl-morpholine;

283)2-(S)-(3-chloro)benzyloxy-3-(S)-phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

284)2-(S)-(3-chloro)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

285)2-(R)-(1-(R)-(3-chloro)phenylethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

286)2-(R)-(1-(R)-(3-chloro)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

287) 2-(S)-(3-chloro)benzyloxy-3-(S)-phenyl-4-(3-(5°oxo-1,2,4-triazolo)methyl-morpholine;

288)2-(S)-(3-chloro)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

289)2-(R)-(1-(R)-(3-chloro)phenylethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

290)2-(R)-(1-(R)-(3-chloro)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

291)2-(S)-(3-chloro)benzyloxy-3-(S)-phenyl-4-(4-(2-oxo-1,3-imidazolo)methyl-morpholine;

292) 2-(S)-(3-chloro)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(4-(2-oxo-1,3-imidazolo)methyl-morpholine;

293)2-(R)-(1-(R)-(3-chloro)phenylethoxy)-3-(S)-phenyl-4-(4-(2-oxo-1,3-imidazolo)methyl-morpholine;

294)2-(R)-(1-(R)-(3-chloro)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(4-(2-oxo-1,3-imidazolo)methyl-morpholine;

295)2-(S)-(3-chloro)benzyloxy-3-(S)-phenyl-4-(2-imidazolo)methyl-morpholine;

296)2-(S)-(3-chloro)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(2-imidazolo)methyl-morpholine;

297)2-(R)-(1-(R)-(3-chloro)phenylethoxy)-3-(S)-phenyl-4-(2-imidazolo)methyl-morpholine;

298)2-(R)-(1-(R)-(3-chloro)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(2-imidazolo)methyl-morpholine;

299)2-(S)-(3-chloro)benzyloxy-3-(S)-phenyl-4-(4-imidazolo)methyl-morpholine;

300)2-(S)-(3-chloro)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(4-imidazolo)methyl-morpholine;

301)2-(R)-(1-(R)-(3-chloro)phenylethoxy)-3-(S)-phenyl-4-(4-imidazolo)methyl-morpholine;

302)2-(R)-(1-(R)-(3-chloro)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(4-imidazolo)methyl-morpholine;

303)2-(S)-(3-chloro)benzyloxy-3-(S)-phenyl-4-(5-tetrazolo)methyl-morpholine;

304) 2-(S)-(3-chloro)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(5-tetrazolo)methyl-morpholine;

305)2-(R)-(1-(R)-(3-chloro)phenylethoxy)-3-(S)-phenyl-4-(5-tetrazolo)methyl-morpholine;

306)2-(R)-(1-(R)-(3-chloro)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(5-tetrazolo)methyl-morpholine;

307) 2-(S)-(3-chloro)benzyloxy-3-(S)-phenyl-4-(2-oxo-5H-pyrrol-4-yl)methyl-morpholine;

308)2-(S)-(3-chloro)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(2-oxo-5H-pyrrol-4-yl)methyl-morpholine;

309)2-(R)-(1-(R)-(3-chloro)phenylethoxy)-3-(S)-phenyl-4-(2-oxo-5H-pyrrol-4-yl)methyl-morpholine;

310)2-(R)-(1-(R)-(3-chloro)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(2-oxo-5H-pyrrol-4-yl)methyl-morpholine;

311) 2-(S)-(3-trifluoromethyl)benzyloxy-3-(S)-phenyl-morpholine;

312)2-(S)-(3-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)phenyl-morpholine;

313)2-(R)-(1-(R)-(3-trifluoromethyl)phenylethoxy)-3-(S)-phenyl-morpholine;

314)2-(R)-(1-(R)-(3-trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-morpholine;

315)2-(S)-(3-trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

316)2-(S)-(3-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

317)2-(R)-(1-(R)-(3-trifluoromethyl)phenylethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

318)2-(R)-(1-(R)-(3-trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

319)2-(S)-(3-trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

320) 2-(S)-(3-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

321)2-(R)-(1-(R)-(3-trifluoromethyl)phenylethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

322)2-(R)-(1-(R)-(3-trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

323) 2-(S)-(3-trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(4-(2-oxo-1,3-imidazolo)methyl-morpholine;

324)2-(S)-(3-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(4-(2-oxo-1,3-imidazolo)methyl-morpholine;

325)2-(R)-(1-(R)-(3-trifluoromethyl)phenylethoxy)-3-(S)-phenyl-4-(4-(2-oxo-1,3-imidazolo)methyl-morpholine;

326)2-(R)-(1-(R)-(3-trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(4-(2-oxo-1,3-imidazolo)methyl-morpholine;

327)2-(S)-(3-trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(2-imidazolo)methyl-morpholine;

328)2-(S)-(3-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(2-imidazolo)methyl-morpholine;

329)2-(R)-(1-(R)-(3-trifluoromethyl)phenylethoxy)-3-(S)-phenyl-4-(2-imidazolo)methyl-morpholine;

330)2-(R)-(1-(R)-(3-trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(2-imidazolo)methyl-morpholine;

331)2-(S)-(3-trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(4-imidazolo)methyl-morpholine;

332)2-(S)-(3-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(4-imidazolo)methyl-morpholine;

333)2-(R)-(1-(R)-(3-trifluoromethyl)phenylethoxy)-3-(S)-phenyl-4-(4-imidazolo)methyl-morpholine;

334)2-(R)-(l-(R)-(3-trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(4-imidazolo)methyl-morpholine;

335)2-(S)-(3-trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(5-tetrazolo)methyl-morpholine;

336)2-(S)-(3-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(5-tetrazolo)methyl-morpholine;

337)2-(R)-(1-(R)-(3-trifluoromethyl)phenylethoxy)-3-(S)-phenyl-4-(5-tetrazolo)methyl-morpholine;

338)2-(R)-(1-(R)-(3-trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(5-tetrazolo)methyl-morpholine;

339)2-(S)-(3-trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(2-oxo-5H-pyrrol-4-yl)methyl-morpholine;

340)2-(S)-(3-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(2-oxo-5H-pyrrol-4-yl)methyl-morpholine;

341)2-(R)-(1-(R)-(3-trifluoromethyl)phenylethoxy)-3-(S)-phenyl-4-(2-oxo-5H-pyrrol-4- yl)methyl-morpholine;

342)2-(R)-(1-(R)-(3-trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(2-oxo-5H-pyrrol-4-yl)methyl-morpholine;

343) 2-(S)-(3-t-butyl)benzyloxy-3-(S)-phenyl-morpholine;

344) 2-(S)-(3-t-butyl)benzyloxy-3-(S)-(4-fluoro)phenyl-morpholine;

345) 2-(R)-(1-(R)-(3-t-butyl)phenylethoxy)-3-(S)-phenyl-morpholine;

346)2-(R)-(1-(R)-(3-t-butyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-morpholine;

347)2-(S)-(3-t-butyl)benzyloxy-3-(S)-phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

348)2-(S)-(3-t-butyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

349)2-(R)-(1-(R)-(3-t-butyl)phenylethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

350)2-(R)-(1-(R)-(3-t-butyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

351)2-(S)-(3-t-butyl)benzyloxy-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

352) 2-(S)-(3-t-butyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

353)2-(R)-(1-(R)-(3-t-butyl)phenylethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

354)2-(R)-(1-(R)-(3-t-butyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

355)2-(S)-(3-t-butyl)benzyloxy-3-(S)-phenyl-4-(4-(2-oxo-1,3-imidazolo)methyl-morpholine;

356)2-(S)-(3-t-butyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(4-(2-oxo-1.3-imidazolo)methyl-morpholine;

357)2-(R)-(1-(R)-(3-t-butyl)phenylethoxy)-3-(S)-phenyl-4-(4-(2-oxo-1,3-imidazolo)methyl-morpholine;

358)2-(R)-(1-(R)-(3-t-butyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(4-(2-oxo-1,3-imidazolo)methyl-morpholine;

359)2-(S)-(3-t-butyl)benzyloxy-3-(S)-phenyl-4-(2-imidazolo)methyl-morpholine;

360)2-(S)-(3-t-butyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(2-imidazolo)methyl-morpholine;

361)2-(R)-(1-(R)-(3-t-butyl)phenylethoxy)-3-(S)-phenyl-4-(2-imidazolo)methyl-morpholine;

362)2-(R)-(1-(R)-(3-t-butyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(2-imidazolo)methyl-morpholine;

363)2-(S)-(3-t-butyl)benzyloxy-3-(S)-phenyl-4-(4-imidazolo)methyl-morpholine;

364)2-(S)-(3-t-butyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(4-imidazolo)methyl-morpholine;

365)2-(R)-(1-(R)-(3-t-butyl)phenylethoxy)-3-(S)-phenyl-4-(4-imidazolo)methyl-morpholine;

366)2-(R)-(1-(R)-(3-t-butyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(4-imidazolo)methyl-morpholine;

367)2-(S)-(3-t-butyl)benzyloxy-3-(S)-phenyl-4-(5-tetrazolo)methyl-morpholine;

368)2-(S)-(3-t-butyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(5-tetrazolo)methyl-morpholine;

369)2-(R)-(1-(R)-(3-t-butyl)phenylethoxy)-3-(S)-phenyl-4-(5-tetrazolo)methyl-morpholine;

370)2-(R)-(1-(R)-(3-t-butyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(5-tetrazolo)methyl-morpholine;

371)2-(S)-(3-t-butyl)benzyloxy-3-(S)-phenyl-4-(2-oxo-5H-pyrrol-4-yl)methyl-morpholine;

372)2-(S)-(3-t-butyl)benzyloxy-3-(S)-(4-fluoro)phenyl-4-(2-oxo-5H-pyrrol-4-yl)methyl-morpholine;

373)2-(R)-(1-(R)-(3-t-butyl)phenylethoxy)-3-(S)-phenyl-4-(2-oxo-5H-pyrrol-4-yl)methyl-morpholine;

374)2-(R)-(1-(R)-(3-t-butyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(2-oxo-5H-pyrrol-4-yl)methyl-morpholine;

375)4-(4-(imidazolo)methyl)-2-(3-(tert-butyl)-5-(trifluoromethyl)benzyloxy)-3-phenyl-morpholine;

376)2-(R)-(2,5-bis(trifluoromethyl)benzoyloxy)-3-(S)-(4-fluorophenyl)-4-benzyl-morpholine;

377)2-(R)-(1-(2,5-bis(trifluoromethyl)phenyl)ethenyloxy)-3-(S)-(4-fluorophenyl)-4-benzyl-morpholine;

378)2-(R)-(1-(R)-(2,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4fluorophenyl)-morpholine;

379)2-(R)-(1-(R)-(2,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

380)2-(R)-(1-(R)-(2,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(1,2,4-triazolo)methyl-morpholine;

381)2-(R)-(1-(R)-(2,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-(2-oxo-1,3-imidazolo)methyl-morpholine;

382) 2-(R)-(1-(R)-(3-(thiomethyl)phenyl)ethoxy)-3-(S)-phenyl-morpholine;

383)2-(R)-(1-(R)-(3-(thiomethylphenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

384)2-(R)-(1-(R)-(3-(thiomethylphenyl)ethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

385)2-(R)-(1-(R)-(3-(thiomethylphenyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

386)2-(R)-(l-(R)-(3-(thiomethyl)-5-(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl-morpholine;

387)2-(R)-(1-(R)-(3-(thiomethyl-5-(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

388)2-(R)-(1-(R)-(3-(thiomethyl-5-(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

389)2-(R)-(1-(R)-(3-(thiomethyl-5-(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

390)2-(R)-(1-(R)-(2,2-(dimethyl)-5-(thiomethyl)-2,3-dihydrobenzofuran-7-yl)ethoxy)-3-(S)-phenyl-morpholine;

391)2-(R)-(1-(R)-(2,2-(dimethyl)-5-(thiomethyl)-2,3-dihydrobenzofuran-7-yl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

392)2-(R)-(1-(R)-(2,2-(dimethyl)-5-(thiomethyl)-2,3-dihydrobenzofuran-7-yl)ethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

393)2-(R)-(1-(R)-(2,2-(dimethyl)-5-(thiomethyl)-2,3-dihydrobenzofuran-7-yl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

394)2-(R)-(1-(R)-(3,5-(dimethoxy)phenyl)ethoxy)-3-(S)-phenyl-morpholine;

395)2-(R)-(1-(R)-(3,5-(dimethoxy)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

396)2-(R)-(1-(R)-(3,5-(dimethoxy)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo)methylomorpholine;

397)2-(R)-(1-(R)-(3,5-(dimethoxy)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

398)2-(R)-(1-(R)-(3-(fluoro)-5-(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-morpholine;

399)2-(R)-(1-(R)-(3-(fluoro)-5-(trifluoromethyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3o(5-oxo-1,2,4-triazolo)methyl-morpholine;

400)2-(R)-(1-(R)-(3-(fluoro)-5-(trifluoromethyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

401)2-(R)-(1-(R)-(3-(fluoro)-5-(trifluoromethyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

402)2-(R)-(1-(R)-(3-(chloro)-5-(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-morpholine;

403)2-(R)-(1-(R)-(3-(chloro)-5-(trifluoromethyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

404)2-(R)-(1-(R)-(3-(chloro)-5-(trifluoromethyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3o(1,2,4-triazolo)methyl-morpholine;

405)2-(R)-(1-(R)-(3-(chloro)-5-(trifluoromethyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

406) 2-(R)-(1o(R)-(3,5-(dimethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-morpholine;

407)2-(R)-(1-(R)-(3,5-(dimethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

408)2-(R)-(1-(R)-(3,5-(dimethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

409)2-(R)-(1-(R)-(3,5-(dimethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

410)2-(R)-(1-(R)-(3-(fluoro)-5-(methyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-morpholine;

411)2-(R)-(1-(R)-(3-(fluoro)-5-(methyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

412)2-(R)-(1-(R)-(3-(fluoro)-5-(methyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4o(3-(1,2,4-triazolo)methyl-morpholine;

413)2-(R)-(1-(R)-(3-(fluoro)-5-(methyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

414)2-(R)-(1-(R)-(3-(chloro)-5-(methyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-morpholine;

415)2-(R)-(1-(R)-(3-(chloro)-5-(methyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

416)2-(R)-(1-(R)-(3-(chloro)-5-(methyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

417)2-(R)-(1-(R)-(3-(chloro)-5-(methyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

418)2-(R)-(1-(R)-(3-(bromo)-5-(methyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-morpholine:

419)2-(R)-(1-(R)-(3-(bromo)-5-(methyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

420)2-(R)-(1-(R)-(3-(bromo)-5-(methyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

421)2-(R)-(1-(R)-(3-(bromo)-5-(methyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

422)2-(R)-(1-(R)-(3-(isopropoxy)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-morpholine;

423)2-(R)-(1-(R)-(3-(isopropoxy)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

424)2-(R)-(1-(R)-(3-(isopropoxy)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

425)2-(R)-(1-(R)-(3-(isopropoxy)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

426)2-(R)-(1-(R)-(3-(isopropoxy)-5-(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-morpholine;

427)2-(R)-(1-(R)-(3-(isopropoxy)-5-(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

428)2-(R)-(1-(R)-(3-(isopropoxy)-5-(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

429) 2-(R)-(1-(R)-(3-(isopropoxy)-5-(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

430)2-(R)-(1-(R)-(3-(chloro)-5-(isopropoxy)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-morpholine;

431)2-(R)-(1-(R)-(3-(chloro)-5-(isopropoxy)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

432)2-(R)-(1-(R)-(3-(chloro)-5-(isopropoxy)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

433)2-(R)-(1-(R)-(3-(chloro)-5-(isopropoxy)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

434)2-(R)-(1-(R)-(3-(fluoro)-5-(isopropoxy)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-morpholine;

435)2-(R)-(1-(R)-(3-(fluoro)-5-(isopropoxy)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

436)2-(R)-(1-(R)-(3-(fluoro)-5-(isopropoxy)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

437)2-(R)-(1-(R)-(3-(fluoro)-5-(isopropoxy)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

438)2-(R)-(1-(R)-(3-(t-butyl)-5-(chloro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-morpholine;

439)2-(R)-(1-(R)-(3-(t-butyl)-5-(chloro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

440)2-(R)-(1-(R)-(3-(t-butyl)-5-(chloro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

441)2-(R)-(1-(R)-(3-(t-butyl)-5-(chloro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

442)2-(R)-(1-(R)-(3-(t-butyl)-5-(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-morpholine;

443)2-(R)-(1-(R)-(3-(t-butyl)-5-(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

444)2-(R)-(1-(R)-(3-(t-butyl)-5-(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

445)2-(R)-(1-(R)-(3-(t-butyl)-5-(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

446)2-(R)-(1-(R)-(3,5-(dimethyl)-4-(fluoro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-morpholine;

447)2-(R)-(1-(R)-(3,5-(dimethyl)-4-(fluoro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

448)2-(R)-(1-(R)-(3,5-(dimethyl)-4-(fluoro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

449)2-(R)-(1-(R)-(3,5-(dimethyl)-4-(fluoro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

450)2-(R)-(1-(R)-(3,5-(dimethyl)-4-(chloro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-morpholine;

451)2-(R)-(1-(R)-(3,5-(dimethyl)-4-(chloro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

452)2-(R)-(1-(R)-(3,5-(dimethyl)-4-(chloro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

453)2-(R)-(1-(R)-(3,5-(dimethyl)-4-(chloro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

454)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-4-(fluoro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-morpholine;

455)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-4-(fluoro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

456)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-4-(fluoro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

457)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-4-(fluoro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

458)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-4-(chloro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-morpholine;

459)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-4-(chloro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

460)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-4-(chloro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

461)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-4-(chloro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

462)2-(R)-(1-(R)-(3,5-(dichloro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-morpholine;

463)2-(R)-(1-(R)-(3,5-(dichloro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

464)2-(R)-(1-(R)-(3,5-(dichloro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

465)2-(R)-(1-(R)-(3,5-(dichloro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

466)2-(R)-(1-(R)-(3,5-(difluoro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-morpholine;

467)2-(R)-(1-(R)-(3,5-(difluoro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

468)2-(R)-(1-(R)-(3,5-(difluoro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

469)2-(R)-(1-(R)-(3,5-(difluoro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

470)2-(R)-(I-(R)-(1-(naphthyl)ethoxy)-3-(S)-(4-fluoro)phenyl-morpholine;

471)2-(R)-(1-(R)-(1-(naphthyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

472)2-(R)-(1-(R)-(1-(naphthyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

473)2-(R)-(I-(R)-(1-(naphthyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

474) 2-(R)-(1-(R)-(1-(4-(fluoro)naphthyl))ethoxy)-3-(S)-(4-fluoro)phenyl-morpholine;

475) 2-(R)-(1-(R)-(1-(4-(fluoro)naphthyl))ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

476)2-(R)-(1-(R)-(1-(4-(fluoro)naphthyl))ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

477)2-(R)-(I-(R)-(1-(4-(fluoro)naphthyl))ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

478)2-(R)-(1-(R)-(1-(3-(fluoro)naphthyl))ethoxy)-3-(S)-(4-fluoro)phenyl-morpholine;

479) 2-(R)-(1-(R)-(1-(3-(fluoro)naphthyl))ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

480)2-(R)-(I-(R)-(1-(3-(fluoro)naphthyl))ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

481) 2-(R)-(1-(R)-(1-(3-(fluoro)naphthyl))ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

482)2-(R)-(l-(R)-(1-(3-(chloro)naphthyl))ethoxy)-3-(S)-(4-fluoro)phenyl-morpholine;

483)2-(R)-(1-(R)-(1-(3-(chloro)naphthyl))ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

484)2-(R)-(I-(R)-(1-(3-(chloro)naphthyl))ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

485)2-(R)-(I-(R)-(1-(3-(chloro)naphthyl))ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

486)2-(R)-(I-(R)-(1-(3-(methyl)naphthyl))ethoxy)-3-(S)-(4-fluoro)phenyl-morpholine;

487)2-(R)-(I-(R)-(1-(3-(methyl)naphthyl))ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

488)2-(R)-(1-(R)-(1-(3-(methyl)naphthyl))ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

489)2-(R)-(I-(R)-(1-(3-(methyl)naphthyl))ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

490)2-(R)-(I-(R)-(1-(3-(trifluoromethyl)naphthyl))ethoxy)-3-(S)-(4-fluoro)phenyl-morpholine;

491) 2-(R)-(1-(R)-(1-(3-(trifluoromethyl)naphthyl))ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

492)2-(R)-(1-(R)-(1-(3-(trifluoromethyl)naphthyl))ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

493) 2-(R)-(1-(R)-(1-(3-(trifluoromethyl)naphthyl))ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

494)2-(R)-(1-(R)-(3-(thiomethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-morpholine;

495)2-(R)-(1-(R)-(3-(thiomethylphenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

496)2-(R)-(1-(R)-(3-(thiomethylphenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

497)2-(R)-(1-(R)-(3-(thiomethylphenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

498)2-(R)-(1-(R)-(3-(thiomethyl)-5-(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-morpholine;

499)2-(R)-(1-(R)-(3-(thiomethyl-5-(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

500)2-(R)-(1-(R)-(3-(thiomethyl-5-(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

501)2-(R)-(1-(R)-(3-(thiomethyl-5-(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

502)2-(R)-(1-(R)-(2,2-(dimethyl)-5-(thiomethyl)-2,3-dihydrobenzofuran-7-yl)ethoxy)-3-(S)-(4-fluoro)phenyl-morpholine;

503)2-(R)-(1-(R)-(2,2-(dimethyl)-5-(thiomethyl)-2,3-dihydrobenzofuran-7-yl)ethoxy)o3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

504)2-(R)-(1-(R)-(2,2-(dimethyl)-5-(thiomethyl)-2,3-dihydrobenzofuran-7-yl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

505)2-(R)-(1-(R)-(2,2-(dimethyl)-5-(thiomethyl)-2,3-dihydrobenzofuran-7-yl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

506)2-(R)-(1-(R)-(3,5-(dimethoxy)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-morpholine;

507)2-(R)-(I-(R)-(3,5-(dimethoxy)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

508)2-(R)-(1-(R)-(3,5-(dimethoxy)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

509)2-(R)-(1-(R)-(3,5-(dimethoxy)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

510) 2-(R)-(1-(R)-(phenyl)ethoxy)-3-(S)-phenyl-morpholine;

511)2-(R)-(1-(R)-(phenyl)ethoxy)-3-(S)-phenyl-4-(3o(5-oxo-1,2,4-triazolo)methyl-morpholine;

512)2-(R)-(1-(R)-(phenyl)ethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

513)2-(R)-(1-(R)-(phenyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

514) 2-(R)-(1-(R)-(phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl morpholine;

515)2-(R)-(1-(R)-(phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

516)2-(R)-(1-(R)-(phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

517)2-(R)-(1-(R)-(phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

518) 2-(R)-(1-(R)-(3-(fluoro)phenyl)ethoxy)-3-(S)-phenyl-morpholine;

519)2-(R)-(1-(R)-(3-(fluoro)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

520)2-(R)-(1-(R)-(3-(fluoro)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

521)2-(R)-(1-(R)-(3-(fluoro)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

522)2-(R)-(1-(R)-(3-(fluoro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-morpholine;

523)2-(R)-(1-(R)-(3-(fluoro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

524)2-(R)-(1-(R)-(3-(fluoro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

525)2-(R)-(1-(R)-(3-(fluoro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

526) 2-(R)-(1-(R)-(4-(fluoro)phenyl)ethoxy)-3-(S)-phenyl-morpholine;

527)2-(R)-(1-(R)-(4-(fluoro)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

528)2-(R)-(1-(R)-(4-(fluoro)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

529)2-(R)-(1-(R)-(4-(fluoro)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

530)2-(R)-(1-(R)-(4-(fluoro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-morpholine;

531)2-(R)-(1-(R)-(4-(fluoro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

532)2-(R)-(1-(R)-(4-(fluoro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

533)2-(R)-(1-(R)-(4-(fluoro)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

534)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(3-fluoro)phenyl-morpholine;

535)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(3-fluoro)phenyl-4o(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

536)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(3-fluoro)phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

537)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(3-fluoro)phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

538)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(3,4-difluoro)phenyl-morpholine;

539)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(3,4-difluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

540)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(3,4-difluoro)phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

541)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(3,4-difluoro)phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

542)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(3,4-dichloro)phenyl-morpholine;

543)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(3,4-dichloro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

544)2o(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(3,4-dichloro)phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

545)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(3,4-dichloro)phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

546)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(3,4-dimethyl)phenyl-morpholine;

547) 2-(R)-(1-(R)-(3,5-hi s(trifluoromethyl)phenyl)ethoxy)-3-(S)-(3,4-dimethyl)phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

548)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(3,4-dimethyl)phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

549)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(3,4-dimethyl)phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

550)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-3,4-methylenedioxyphenyl-morpholine;

551)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-3,4-methylenedioxyphenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

552)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-3,4-methylenedioxyphenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

553)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-3,4methylenedioxyphenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

554)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(2naphthyl)-morpholine;

555)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(2-naphthyl)-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine;

556)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(2-naphthyl)-4-(3-(1,2,4-triazolo)methyl-morpholine;

557)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(2-naphthyl)-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

558)2-(R)-(1-(R)-(3-(fluoro)-5-(trifluoromethyl)ethoxy)-3-(S)-phenyl-4-(3-(-1,2,4-triazolo)methyl-morpholine;

559)2-(R)-(1-(R)-(3-(fluoro)-5-(trifluoromethyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

560)2-(R)-(1-(R)-(3-(chloro)-5-(trifluoromethyl)ethoxy)-3-(S)phenyl-4-(3-(-1,2,4-triazolo)methyl-morpholine;

561)2-(R)-(1-(R)-(3-(chloro)-5-(trifluoromethyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

562)2-(R)-(1-(R)-(3,5-(dimethyl)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

563) 2-(R)-(1-(R)-(3,5-(dimethyl)phenyl)ethoxy)-3-(S)-phenyl-4-(3(2-oxo-1,3-imidazolo)methyl-morpholine;

564)2-(R)-(1-(R)-(3-(fluoro)-5-(methyl)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(-1,2,4-triazolo)methyl-morpholine;

565)2-(R)-(1-(R)-(3-(fluoro)-5-(methyl)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

566)2-(R)-(1-(R)-(3-(chloro)-5-(methyl)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(-1,2,4-triazolo)methyl-morpholine;

567)2-(R)-(1-(R)-(3-(chloro)-5-(methyl)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

568)2-(R)-(1-(R)-(3-(bromo)-5-(methyl)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(-1,2,4-triazolo)methyl-morpholine;

569)2-(R)-(1-(R)-(3-(bromo)-5-(methyl)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

570)2-(R)-(1-(R)-(3-(isopropoxy)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(1.2,4-triazolo)methyl-morpholine;

571)2-(R)-(1-(R)-(3-(isopropoxy)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

572)2-(R)-(l-(R)-(3-(isopropoxy)-5-(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(-1,2,4-triazolo)methyl-morpholine;

573)2-(R)-(1-(R)-(3-(isopropoxy)-5-(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

574)2-(R)-(1-(R)-(3-(chloro)-5-(isopropoxy)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(-1,2,4-triazolo)methyl-morpholine;

575)2-(R)-(1-(R)-(3-(chloro)-5-(isopropoxy)phenyl)ethoxy)-3-(S)phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

576)2-(R)-(1-(R)-(3-(fluoro)-5-(isopropoxy)phenyl)ethoxy)-3-(S)phenyl-4-(3-(-1,2,4-triazolo)methyl-morpholine;

577)2-(R)-(1-(R)-(3-(fluoro)-5-(isopropoxy)phenyl)ethoxy)-3-(S)phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

578)2-(R)-(1-(R)-(3-(t-butyl)-5-(chloro)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(-1,2,4-triazolo)methyl-morpholine;

579)2-(R)-(1-(R)-(3-(t-butyl)-5-(chloro)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

580)2-(R)-(1-(R)-(3-(t-butyl)-5-(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(-1,2,4-triazolo)methyl-morpholine;

581)2-(R)-(1-(R)-(3-(t-butyl)-5-(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

582)2-(R)-(1-(R)-(3,5-(dimethyl)-4-(fluoro)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(-1,2,4-triazolo)methyl-morpholine;

583)2-(R)-(1-(R)-(3,5-(dimethyl)-4-(fluoro)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

584)2-(R)-(1-(R)-(3,5-(dimethyl)-4-(chloro)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(-1,2,4-triazolo)methyl-morpholine;

585)2-(R)-(1-(R)-(3,5-(dimethyl)-4-(chloro)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

586)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-4-(fluoro)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(-1,2,4-triazolo)methyl-morpholine;

587)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-4-(fluoro)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

588)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-4-(chloro)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(-1,2,4-triazolo)methyl-morpholine;

589)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-4-(chloro)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

590)2-(R)-(1-(R)-(3,5-(dichloro)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

591)2-(R)-(1-(R)-(3,5-(dichloro)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

592)2-(R)-(1-(R)-(3,5-(difluoro)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo)methyl-morpholine;

593)2-(R)-(1-(R)-(3,5-(difluoro)phenyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

594)2-(R)-(1-(R)-(1-(naphthyl)ethoxy)-3-(S)-phenyl-4-(3-(-1,2,4-triazolo)methyl-morpholine;

595)2-(R)-(1-(R)-(1-(naphthyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

596)2-(R)-(I-(R)-(1-(4-(fluoro)naphthyl))ethoxy)-3-(S)-phenyl-4-(3-(-1,2,4-triazolo)methyl-morpholine;

597)2-(R)-(1-(R)-(1-(4-(fluoro)naphthyl))ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

598)2-(R)-(1-(R)-(1-(3-(fluoro)naphthyl))ethoxy)-3-(S)-phenyl-4-(3-(-1,2,4-triazolo)methyl-morpholine;

599)2-(R)-(1-(R)-(1-(3-(fluoro)naphthyl))ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

600)2-(R)-(I-(R)-(1-(3-(chloro)naphthyl))ethoxy)-3-(S)-phenyl-4-(3-(-1,2,4-triazolo)methyl-morpholine;

601)2-(R)-(I-(R)-(1-(3-(chloro)naphthyl))ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)methyl-morpholine;

or a pharmaceutically acceptable salt thereof.

Specific compounds within the scope of the present invention include:

(1)2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholineN-oxide;

(2)2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-4-(3-(4-(ethoxycarbonyloxy-1-ethyl)5-oxo-1H,-1,2,4-triazolo)methyl)morpholine:

(3)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(4-monophosphoryl-5-oxo-1H,-1,2,4triazolo)methyl)morpholine;

(4)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(1-monophosphoryl-5-oxo-1H,-1,2,4triazolo)methyl)morpholine;

(5)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(2-monophosphoryl-5-oxo-1H,-1,2,4triazolo)methyl)morpholine;

(6)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(5-oxyphosphoryl-1H,-1,2,4-triazolo)methyl)morpholine;

or a pharmaceutically acceptable salt thereof.

Specific compounds within the scope of the present invention alsoinclude: ##STR9## or a pharmaceutically acceptable salt thereof.

TACHYKININ ANTAGONISM ASSAY

The compounds of this invention are useful for antagonizing tachykinins,in particular substance P and neurokinin A in the treatment ofgastrointestinal disorders, central nervous system disorders,inflammatory diseases, pain or migraine and asthma in a mammal in needof such treatment. This activity can be demonstrated by the followingassay.

A. Receptor Expression in COS

To express the cloned human neurokinin-1 receptor (NK1R) transiently inCOS, the cDNA for the human NK1R was cloned into the expression vectorpCDM9 which was derived from pCDM8 (INVITROGEN) by inserting theampicillin resistance gene (nucleotide 1973 to 2964 from BLUESCRIPT SK+)into the Sac II site. Transfection of 20 ug of the plasmid DNA into 10million COS cells was achieved by electroporation in 800 ul oftransfection buffer (135 mM NaCl, 1.2 mM CaCl₂, 1.2 mM MgCl₂, 2.4 mM K₂HPO₄, 0.6 mM KH₂ PO₄, 10 mM glucose, 10 mM HEPES pH 7.4) at 260 V and950 uF using the IBI GENEZAPPER (IBI, New Haven, Conn.). The cells wereincubated in 10% fetal calf serum, 2 mM glutamine, 100U/ml penicillinstreptomycin, and 90% DMEM media (GIBCO, Grand Island, N.Y.) in 5% CO₂at 37° C. for three days before the binding assay.

B. Stable Expression in CHO

To establish a stable cell line expressing the cloned human NK1R, thecDNA was subcloned into the vector pRcCMV (INVITROGEN). Transfection of20 ug of the plasmid DNA into CHO cells was achieved by electroporationin 800 ul of transfection buffer suplemented with 0.625 mg/ml Herringsperm DNA at 300 V and 950 uF using the IBI GENEZAPPER (IBI). Thetransfected cells were incubated in CHO media 10 % fetal calf serum, 100U/ml pennicilin-streptomycin, 2 mM glutamine, 1/500hypoxanthine-thymidine (ATCC), 90% IMDM media (JRH BIOSCIENCES, Lenexa,Kan.), 0.7 mg/ml G418 (GIBCO)!in 5% CO₂ at 37° C. until colonies werevisible. Each colony was separated and propagated. The cell clone withthe highest number of human NK 1R was selected for subsequentapplications such as drug screening.

C. Assay Protocol using COS or CHO

The binding assay of human NK1R expressed in either COS or CHO cells isbased on the use of 125I-substance P (125I-SP, from DU PONT, Boston,Mass.) as a radioactively labeled ligand which competes with unlabeledsubstance P or any other ligand for binding to the human NK 1R.Monolayer cell cultures of COS or CHO were dissociated by thenon-enzymatic solution (SPECIALTY MEDIA, Lavallette, N.J.) andresuspended in appropriate volume of the binding buffer (50 mM Tris pH7.5, 5 mM MnCl₂, 150 mM NaCl, 0.04 mg/ml bacitracin, 0.004 mg/mlleupeptin, 0.2 mg/ml BSA, 0.01 mM phosphoramidon) such that 200 ul ofthe cell suspension would give rise to about 10,000 cpm of specific ¹²⁵I-SP binding (approximately 50,000 to 200,000 cells). In the bindingassay, 200 ul of cells were added to a tube containing 20 ul of 1.5 to2.5 nM of ¹²⁵¹ -SP and 20 ul of unlabeled substance P or any other testcompound. The tubes were incubated at 4° C. or at room temperature for 1hour with gentle shaking. The bound radioactivity was separated fromunbound radioactivity by GF/C filter (BRANDEL, Gaithersburg, Md.) whichwas pre-wetted with 0.1% polyethylenimine. The filter was washed with 3ml of wash buffer (50 mM Tris pH 7.5, 5 mM MnCl₂, 150 mM NaCl) threetimes and its radioactivity was determined by gamma counter.

The activation of phospholipase C by NKIR may also be measured in CHOcells expressing the human NK1R by determining the accumulation ofinositol monophosphate which is a degradation product of IP₃. CHO cellsare seeded in 12-well plate at 250,000 cells per well. After incubatingin CHO media for 4 days, cells are loaded with 0.025 uCi/ml of ³H-myoinositol by overnight incubation. The extracellular radioactivityis removed by washing with phosphate buffered saline. LiCI is added tothe well at final concentration of 0.1 mM with or without the testcompound, and incubation is continued at 37° C. for 15 min. Substance Pis added to the well at final concentration of 0.3 nM to activate thehuman NK 1R. After 30 min of incubation at 37° C., the media is removedand 0.1 N HCl is added. Each well is sonicated at 4° C. and extractedwith CHCl₃ /methanol (1:1). The aqueous phase is applied to a 1 ml DowexAG 1×8 ion exchange column. The column is washed with 0.1N formic acidfollowed by 0.025M ammonium formate-0.1N formic acid. The inositolmonophosphate is eluted with 0.2M ammonium formate-0.1N formic acid andquantitated by beta counter.

The compounds of the present invention are useful in the prevention andtreatment of a wide variety of clinical conditions which arecharacterized by the presence of an excess of tachykinin, in particularsubstance P, activity.

These conditions may include disorders of the central nervous systemsuch as anxiety, depression, psychosis and schizophrenia;neurodegenerative disorders such as AIDS related dementia, seniledementia of the Alzheimer type, Alzheimer's disease and Down's syndrome;demyelinating diseases such as multiple sclerosis (MS) and amyotrophiclateral sclerosis (ALS; Lou Gehrig's disease) and otherneuropathological disorders such as peripheral neuropathy, for s exampleAIDS related neuropathy, diabetic neuropathy, chemotherapy-inducedneuropathy, and postherpetic and other neuralgias; respiratory diseasessuch as chronic obstructive airways disease, bronchopneumonia, chronicbronchitis, bronchospasm and asthma; airways disease modulated byneurogenic inflammation; diseases characterized by neurogenic mucussecretion, such as cystic fibrosis; diseases associated with decreasedglandular secretions, including lacrimation, such as Sjogren's syndrome,hyperlipoproteinemias IV and V, hemochromatosis, sarcoidosis, oramyloidosis; inflammatory diseases such as inflammatory bowel disease,irritable bowel syndrome, psoriasis, fibrositis, ocular inflammation,osteoarthritis and rheumatoid arthritis; allergies such as eczema andrhinitis; hypersensitivity disorders such as poison ivy; ophthalmicdiseases such as conjunctivitis, vernal conjunctivitis, dry eyesyndrome, and the like; cutaneous diseases such as contact dermatitis,atropic dermatitis, urticaria, and other eczematoid dermatitis; oedema,such as oedema caused by thermal injury; addiction disorders such asalcholism; stress related somatic disorders; reflex sympatheticdystrophy such as shoulder/hand syndrome; dysthymic disorders; adverseimmunological reactions such as rejection of transplanted tissues anddisorders related to immune enhancement or suppression, such as systemiclupus erythematosis; gastrointestinal (GI) disorders and diseases of theGI tract such as disorders associated with the neuronal control ofviscera such as ulcerative colitis, Crohn's disease and incontinence;emesis, including acute, delayed, post-operative, late-phase, andanticipatory emesis, for example, induced by chemotherapy, radiation,toxins, pregnancy, vestibular disorder, motion, post-operative sickness,surgery, gastrointestinal obstruction, reduced gastrointestinalmotility, visceral pain, migraine, opioid analgesics and variations inintercranial pressure (except quaternary salts); disorders of bladderfunction such as bladder detrusor hyperreflexia; fibrosing and collagendiseases such as scleroderma and eosinophilic fascioliasis; disorders ofblood flow caused by vasodilation and vasospastic diseases such asangina, migraine and Reynaud's disease; and pain or nociception, forexample, chronic pain or that attributable to or associated with any ofthe foregoing conditions especially the transmission of pain inmigraine. Hence, these compounds may be readily adapted to therapeuticuse for the treatment of physiological disorders associated with anexcessive stimulation of tachykinin receptors, especially neurokinin-1,and as neurokinin-1 antagonists in the control and/or treatment of anyof the aforesaid clinical conditions in mammals, including humans.

For example, the compounds of the present invention may suitably be usedin the prevention or treatment of disorders of the central nervoussystem such as anxiety, psychosis and schizophrenia; neurodegenerativedisorders such as senile dementia of the Alzheimer type, Alzheimer'sdisease and Down's syndrome; respiratory diseases, particularly thoseassociated with excess mucus secretion, such as chronic obstructiveairways disease, broncho-pneumonia, chronic bronchitis, cystic fibrosisand asthma, and bronchospasm; inflammatory diseases such as inflammatorybowel disease, osteoarthritis and rheumatoid arthritis; adverseimmunological reactions such as rejection of transplanted tissues;gastrointestinal (GI) disorders and diseases of the GI tract such asdisorders associated with the neuronal control of viscera such asulcerative colitis, Crohn's disease and incontinence; disorders of bloodflow caused by vasodilation; and pain or nociception, for example, thatattributable to or associated with any of the foregoing conditions orthe transmission of pain in migraine (both prophylaxis and acutetreatment).

As calcium channel blocking agents some of the compounds of the presentinvention are useful in the prevention of treatment of clinicalconditions which benefit from inhibition of the transfer of calcium ionsacross the plasma membrane of cells. These include diseases anddisorders of the heart and vascular system such as angina pectoris,myocardial infarction, cardiac arrhythmia, cardiac hypertrophy, cardiacvasospasm, hypertension, cerebrovascular spasm and other ischemicdisease. Furthermore, these compounds may be capable of loweringelevated intraocular pressure when administered topically to thehypertensive eye in solution in a suitable ophthalmic vehicle. Also,these compounds may be useful in the reversal of multidrug resistance intumor cells by enhancing the efficacy of chemotherapeutic agents. Inaddition, these compounds may have activity in blocking calcium channelsin insect brain membranes and so may be useful as insecticides.

The compounds of the present invention are particularly useful in thetreatment of pain or nociception and/or inflammation and disordersassociated therewith such as, for example: neuropathy, such as diabeticor peripheral neuropathy and chemotherapy-induced neuropathy;postherpetic and other neuralgias; asthma; osteoarthritis; rheumatoidarthritis; and especially migraine. The compounds of the presentinvention are also particularly useful in the treatment of diseasescharacterized by neurogenic mucus secretion, especially cystic fibrosis.

In the treatment of the clinical conditions noted above, the compoundsof this invention may be utilized in compositions such as tablets,capsules or elixirs for oral administration, suppositories for rectaladministration, sterile solutions or suspensions for parenteral orintramuscular administration, and the like.

The pharmaceutical compositions of this invention can be used in theform of a pharmaceutical preparation, for example, in solid, semisolidor liquid form, which contains one or more of the compounds of thepresent invention, as an active ingredient, in admixture with an organicor inorganic carrier or excipient suitable for external, enteral orparenteral applications. The active ingredient may be compounded, forexample, with the usual non- toxic, pharmaceutically acceptable carriersfor tablets, pellets, capsules, suppositories, solutions, emulsions,suspensions, and any other form suitable for use. The carriers which canbe used are water, glucose, lactose, gum acacia, gelatin, mannitol,starch paste, magnesium trisilicate, talc, corn starch, keratin,colloidal silica, potato starch, urea and other carriers suitable foruse in manufacturing preparations, in solid, semisolid, or liquid form,and in addition auxiliary, stabilizing, thickening and coloring agentsand perfumes may be used. The active object compound is included in thepharmaceutical composition in an amount sufficient to produce thedesired effect upon the process or condition of the disease.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical carrier, e.g. conventionaltableting ingredients such as corn starch, lactose, sucrose, sorbitol,talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, andother pharmaceutical diluents, e.g. water, to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention, or a non-toxic pharmaceuticallyacceptable salt thereof. When referring to these preformulationcompositions as homogeneous, it is meant that the active ingredient isdispersed evenly throughout the composition so that the composition maybe readily subdivided into equally effective unit dosage forms such astablets, pills and capsules. This solid preformulation composition isthen subdivided into unit dosage forms of the type described abovecontaining from 0.1 to about 500 mg of the active ingredient of thepresent invention. The tablets or pills of the novel composition can becoated or otherwise compounded to provide a dosage form affording theadvantage of prolonged action. For example, the tablet or pill cancomprise an inner dosage and an outer dosage component, the latter beingin the form of an envelope over the former. The two components can beseparated by an enteric layer which serves to resist disintegration inthe stomach and permits the inner component to pass intact into theduodenum or to be delayed in release. A variety of materials can be usedfor such enteric layers or coatings, such materials including a numberof polymeric acids and mixtures of polymeric acids with such materialsas shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solution, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinylpyrrolidone or gelatin.

Compositions for inhalation or insuffiation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as set outabove. Preferably the compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably sterile pharmaceutically acceptable solvents may be nebulizedby use of inert gases. Nebulized solutions may be breathed directly fromthe nebulizing device or the nebulizing device may be attached to a facemask, tent or intermittent positive pressure breathing machine.Solution, suspension or powder compositions may be administered,preferably orally or nasally, from devices which deliver the formulationin an appropriate manner.

For the treatment of the clinical conditions and diseases noted above,the compounds of this invention may be administered orally, topically,parenterally, by inhalation spray or rectally in dosage unitformulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques.

For the treatment of certain conditions it may be desirable to employ acompound of the present invention in conjunction with anotherpharmacologically active agent. For example, for the treatment ofrespiratory diseases such as asthma, a compound of the present inventionmay be used in conjunction with a bronchodilator, such as a β₂-adrenergic receptor agonist or tachykinin antagonist which acts atneurokinin-2 receptors. Also, for the treatment of conditions thatrequire antagonism of both neurokinin-I and neurokinin-2, includingdisorders associated with bronchoconstriction and/or plasmaextravasation in airways, such as asthma, chronic bronchitis, airwaysdisease, or cystic fibrosis, a compound of the present invention may beused in conjunction with a tachykinin antagonist which acts atneurokinin-2 receptors, or with tachykinin receptor antagonist whichacts at both neurokinin-1 and neurokinin-2 receptors. Similarly, for theprevention or treatment of emesis a compound of the present inventionmay be used in conjunction with other anti-emetic agents, especially5HT₃ receptor antagonists, such as ondansetron, granisetron,tropisetron, decadron, and zatisetron. Likewise, for the prevention ortreatment of migraine a compound of the present invention may be used inconjunction with other anti-migraine agents, such as ergotamines or 5HT₁agonists, especially sumatriptan. For the prevention or treatment ofinflammatory conditions in the lower urinary tract, especially cystitis,a compound of the present invention may be used in conjunction with anantiinflammatory, such as a bradykinin receptor antagonist. The compoundof the present invention and the other pharmacologically active agentmay be administered to a patient simultaneously, sequentially or incombination.

The compounds of this invention may be administered to patients (animalsand human) in need of such treatment in dosages that will provideoptimal pharmaceutical efficacy. The dose will vary from patient topatient depending upon the nature and severity of disease, the patient'sweight, special diets then being followed by a patient, concurrentmedication, and other factors which those skilled in the art willrecognize.

In the treatment of a condition associated with an excess oftachykinins, an appropriate dosage level will generally be about 0.001to 50 mg per kg patient body weight per day which can be administered insingle or multiple doses. Preferably, the dosage level will be about0.005 to about 25 mg/kg per day; more preferably about 0.01 to about 10mg/kg per day; and even more preferably about 0.05 to about 5 mg/kg perday. For example, in the treatment of conditions involving theneurotransmission of pain sensations, a suitable dosage level is about0.001 to 25 mg/kg per day, preferably about 0.005 to 10 mg/kg per day,and especially about 0.01 to 5 mg/kg per day. The compounds may beadministered on a regimen of 1 to 4 times per day, preferably once ortwice per day.

Several methods for preparing the compounds of this invention areillustrated in the following Schemes and Examples wherein wherein R²,R³, R⁶, R⁷, R⁸, R¹¹, R¹², R¹³, A, B, p, Y and Z are as defined above.

                  TABLE 1    ______________________________________    Reagents:    Et.sub.3 N triethylamine    Ph.sub.3 P triphenylphosphine    TFA        trifluoroacetic acid    NaOEt      sodium ethoxide    DCC        N,N'-dicyclohexylcarbodiimide    DCU        N,N'-dicyclohexylurea    CDI        1,1'-carbonyldiimidazole    MCPBA      m-chloroperbenzoic acid    DBU        1,8-diazabicyclo 5.4.0!undec-7-ene    Cbz-Cl     benzyl chloroformate    ACE-Cl     alpha-chloroethyl chloroformate    iPr.sub.2 NEt or DIEA               N,N-diisopropylethylamine    NHS        N-hydroxysuccinimide    DIBAL      diisobutylaluminum hydride    Me.sub.2 SO.sub.4               dimethyl sulfate    HOBt       1-hydroxybenzotriazole hydrate    EDAC       1-ethyl-3-(3-dimethylaminopropyl)carbo-               diimide hydrochloride    Solvents:    DMF        dimethylformamide    THF        tetrahydrofuran    MeOH       methanol    EtOH       ethanol    AmOH       n-amyl alcohol    AcOH       acetic acid    MeCN       acetonitrile    DMSO       dimethylsulfoxide    Others:    Ph         phenyl    Ar         aryl    Me         methyl    Et         ethyl    iPr        isopropyl    Am         n-amyl    Cbz        carbobenzyloxy (benzyloxy-carbonyl)    BOC        tert-butoxycarbonyl    PTC        phase transfer catalyst    cat.       catalytic    FAB-MS     fast atom bombardment mass spectrometry    rt         room temperature    LG         leaving group (Cl, Br, I, OTs, OMs,               OTf, etc.)    ______________________________________     ##STR10##

The compounds of the present invention in which Y=0 may be prepared bythe general route outlined in Scheme 1. Thus, the appropriatelysubstituted α-bromo-phenylacetaldehyde, dimethyl acetal I (preparedusing the method of Jacobs in Journal of the American Chemical Society,1953, 75, 5500) may be converted to the dibenzyl acetal II by stirring Iand a slight excess of a benzyl alcohol in the presence of an acidcatalyst with concommitant removal of methanol. Alkylation of asubstituted amino alcohol by benzyl bromide II may give N-alkyl aminoalcohol III; use of a chiral amino alcohol would result in the formationof diastereomers and these may be separated at this (or at a later)stage using standard chromatographic methods. N-Alkylation orN-acylation of III may give the dialkyl- or acyl/alkylamino alcohol IVin which the group A--B may serve as a protecting group or be used as orelaborated into a substituent in the final target compound. Cyclizationto give substituted morpholine V may be realized by warming a solutionof IV and an acid catalyst. Diastereomers of V that may be formed may beseparated using standard chromatographic methods. If A--B is aprotecting group, it may be removed using known procedures (Greene, T.W., Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed., JohnWiley & Sons, Inc., New York, 1991 ). If the preparation of I-V resultsin the formation of enantiomers, these may be resolved by alkylating oracylating V (A--B=H) with a chiral auxiliary, separating thediastereomers thus formed using known chromatographic methods, andremoving the chiral auxiliary to give the enantiomers of V.Alternatively, the diastereomers of V may be separated via fractionalcrystallization from a suitable solvent of the diastereomeric saltsformed by V and a chiral organic acid.

The compounds of the present invention in which Y=CH₂ may be prepared bythe general route outlined in Scheme 2. Thus, the N-methoxy-N-methylamide of a protected phenyl glycine VI (prepared from the carboxylicacid via the mixed anhydride according to the procedure of Rapoport inJournal of Organic Chemistry, 1985, 50, 3972) may be used to acylate thelithium enolate of methyl diethylphosphonate to give the ketophosphonateVII. The sodium salt of VII may be condensed with an appropriatelysubstituted benzaldehyde to give the α,β-unsaturated ketone VIII.Reduction of the ketone and removal of the t-butylcarbamate protectinggroup may give amino alcohol IX; diastereomers that may form may beseparated at this (or at a later) stage using standard chromatographictechniques. Williamson etherification of IX using a substitutedchloroacetate, followed by warming, may result in the formation ofmorpholinone X. Reduction of the double bond and amide carbonyl may beaccomplished in a straightforward manner to give the substitutedmorpholine XI. If the preparation of VI-XI results in the formation ofenantiomers, these may be resolved by alkylating or acylating XI(A--B=H) with a chiral auxiliary, separating the diastereomers thusformed using known chromatographic methods, and removing the chiralauxiliary to give the enantiomers of XI. Alternatively, thediastereomers of XI may be separated via fractional crystallization froma suitable solvent of the diastereomeric salts formed by XI and a chiralorganic acid. If it is desired that A--B is other than H, the morpholinenitrogen of XI may be further functionalized using standard methods forthe alkylation or acylation of secondary amines. If it is desired thatR² is other than H, morpholinone X may be elaborated into thecarbinolcarbamate (A--B =RO₂ C, R² =OH), an intermediate that could bealkylated and would allow for variation in R².

The compounds of the present invention in which Y=0 may also be preparedby the general route outlined in Scheme 3. Thus, the appropriatelysubstituted a-bromo-acetaldehyde, dimethyl acetal (prepared using themethod of Jacobs in Journal of the American Chemical Society, 1953, 75,5500) may be convened to the acetal by stirring and a slight excess ofthe appropriate alcohol in the presence of an acid catalyst withconcommitant removal of methanol. Alkylation of a substituted aminoalcohol by a bromide may give the N-alkyl amino alcohol: use of a chiralamino alcohol would result in the formation of diastereomers and thesemay be separated at this (or at a later) stage using standardchromatographic methods. N-Alkylation or N-acylation may give thedialkyl- or acyl/alkyl-amino alcohol in which the group A--B may serveas a protecting group or be used as or elaborated into a substituent inthe final target compound. Cyclization to give substituted morpholinemay be realized by warming a solution with an acid catalyst.Diastereomers that may be formed may be separated using standardchromatographic methods. If A--B is a protecting group, it may beremoved using known procedures (Greene, T. W., Wuts, P. G. M. ProtectiveGroups in Organic Synthesis, 2nd ed., John Wiley & Sons, Inc., New York,1991 ). If the preparation of such compounds results in the formation ofenantiomers, these may be resolved by alkylating or acylating the finalproduct (A--B=H) with a chiral auxiliary, separating the diastereomersthus formed using known chromatographic methods, and removing the chiralauxiliary to give the desired enantiomers. Alternatively, thediastereomers may be separated via fractional crystallization from asuitable solvent of the diastereomeric salts formed by the compound of achiral organic acid.

One method of synthesizing enantiomerically pure substituted morpholinesis illustrated in Scheme 4. Protection of enantiomerically purephenylglycine as the N-benzyl derivative followed by double alkylationwith a 1,2-dibromoethane derivative leads to the morpholinone. Reductionwith an active hydride reagent such as diisobutyl aluminum hydride,lithium aluminum hydride, lithium tri(sec-butyl)-borohydride(L-Selectride®) or other reducing agents leads predominantly to the2,3-transmorpholine derivatives. Alkylation of the alcohol, rentoval ofthe protecting group on nitrogen (for example, with a palladiumhydrogenation catalyst or with 1-chloroethyl chloroformate (Olofson inJ. Org. Chem., 1984, 2081 and 2795), and alkylation of the nitrogen(wherein in A--B--CH₂ -- or A--B--CHO═ appropriate definitions of A--Bare present) produces the 2,3-trans compounds.

One method of producing enantiomerically pure 2,3-cis morpholines isillustrated in Scheme 5. In the first step, formation of thetrifluoromethane-sulfonate ester of the appropiate benzyl alcohol(especially benzyl alcohols which are substituted withelectron-withdrawing groups such as --NO₂, --F, --Cl, --Br, --COR,--CF₃, etc) is carried out in the presence of an unreactive base, in aninert solvent. Other leaving groups such as iodide, mesylate, tosylate,p-nitrophenylsulfonate and the like may also be employed. Appropriatebases include 2,6-di-t-butylpyridine, 2,6-di-t-butyl-4-methyl-pyridine,diisopropylethylamine, potassium carbonate, sodium carbonate, and thelike. Suitable solvents include toluene, hexanes, benzene, carbontetrachloride. dichloromethane, chloroform, dichloroethane, and the likeand mixtures thereof. The filtered solution of the triflate is thenadded to a solution of the intermediate formed when the morpholinone iscontacted with an active hydride reagent such as diisobutyl aluminumhydride, lithium aluminum hydride, or lithium tri(sec-butyl)-borohydride (L-Selectride®) at low temperature, preferably from -78° C.to -20° C. After several hours at low temperature, workup andpurification provides predominantly 2,3-cis substituted products, whichmay be carried on to final compounds as shown in Scheme 5.

Enantiomerically pure phenylglycines substituted on the phenyl ring maybe prepared by the procedure shown in Scheme 6 (D. A. Evans, et al, J,Am. Chem. Soc., 990, 112, 4011).

Methods for preparing the nitrogen alkylating agents A--B--CH₂ --LG(wherein "LG" indicates an appropriately suitable leaving group) used inScheme 4 and Scheme 5 are based on known literature methods (forA--B=3-(1,2,4-triazolyl) or 5-(1,2,4-triazol-3-one)-yl and LG=Cl, seeYanagisawa, I.; Hirata, Y.; Ishii, Y. Journal of Medicinal Chemistry,27, 849 (1984); for A--B=4-((2H)-imidazol-2-one)-yl or5-(4-ethoxycarbonyl-(2H)-imidazol-2-one)-yl and X=Br, see Ducschinsky,R., Dolan, L. A. Journal of the American Chemical Society, 70, 657(1948)).

One method of producing enantiomerically pure 2,3-cis morpholines thatare substituted at the α-position of the C2 benzyl ether is shown inScheme 7. Thus, a substituted 2-morpholinone (prepared as described inScheme 4) is reacted with an active hydride reagent, such asdiisobutylaluminum hydride, lithium aluminum hydride, or lithiumtri(sec-butyl)borohydride and the resulting reaction intermediate isquenched with a substituted benzoyl halide, anhydride, or otheractivated acyl transfer reagent. Aqueous work-up affords the2-benzoyloxy compound shown in Scheme 7. This compound is convened tothe corresponding enol ether using a "titanium ylide" generated fromreagents such as μ-chloro-μ-methylene-bis(cyclopentadienyl)titanium!dimethylaluminum ("Tebbe Reagent", Tebbe,F. N., Parshall, G. W., Reddy, G. S., Journal of the American Society,100, 3611 (1978)), dimethyl titanocene (Petasis, N. A., Bzowej, E. I.,Journal of the American Chemical Society, 112, 6392 (1990)) or thereagent prepared by the reduction of 1,1-dibromoalkanes with zinc andtitanium tetrachloride in the presence ofN,N,N',N'-tetramethylethylenediamine (Takai, K. et. al., Journal ofOrganic Chemistry, 52, 4412 (1987)). The resulting enol ether is reducedto its saturated analog by hydrogenation in the presence of a rhodiumbased catalyst, such as rhodium on alumina or on carbon: if concomitantremoval of the N-benzyl group on the morpholine nitrogen is desired, thehydrogenation may be carried out in the presence of palladium on carboncatalyst. If diastereomers are obtained at this juncture, they may beseparated using chromatographic methods or by recrystallization of themixture of diastereomers. Elaboration of the morpholines so obtained tothe final product is carried out in manners analogous to those describedin Schemes 4 and 5.

Methods by which the substitution on the C-3 phenyl ring of themorpholines of the present invention may be introduced or altered isshown in Scheme 8. Thus, a substituted morpholine may be prepared asdescribed in Scheme 4, 5, or 7 from an enantiomerically purebenzyloxy-substituted aryl glycine (prepared as described in theliterature (e.g. L-p-benzyloxyphenylglycine may be prepared according tothe procedure of Kamiya, et al. Tetrahedron, 35, 323 (1979)) or usingthe methods described in Scheme 6). Selective cleavage of the benzylether via hydrogenolysis or nonselective hydrogenolysis followed by thesynthetic sequence shown in Scheme 8 may afford a suitably protectedphenolic intermediate. The phenol may be converted to the correspondingaryl triflate (as shown, or using N-phenyl-trifluoromethane-sulfonimidein the presence of a tertiary amine base in methylene chloride) and thetriflate convened to the desired functional group using the palladium-or nickel-catalyzed methods described in Ritter, Synthesis, 735 (1993)(and refs. therein). Elaboration to the desired final product may becarried out as described in Scheme 4 or 5.

The parent compounds prepared above are convened to their prodrugcounterparts by alkylation, acylation, phosphorylation or sulfonylationto give ether, ester, phosphate or sulfonate derivatives (wherein theparent compounds bear an -X substitutent as defined above) by thegeneral procedures referenced herein, or reasonable modificationsthereof.

In particular, as depicted in Scheme 9, treatment of, for example, atriazolone or imidazolone-containing tachykinin antagonist with asuitable base, such as n-butyllithium, sodium hydride, potassiumhydride, lithium hexamethyldisilazide, sodium hexamethyldisilazide,potassium hexamethyldisilazide or lithium diisopropylamide in THF at lowtemperature followed by addition of an appropiate phosphoryl transferreagent, for example tetrabenzyl pyrophosphate, dibenzylphosphochloridate or dibenzyl phosphofluoridate provides an intermediatewith a protected phosphoryl group. Following purification, for exampleby gravity silica gel chromatography or by reverse phase high pressureliquid chromatography, the dibenzyl ester may be convened into thedesired product by hydrogenolysis, for example with hydrogen gas in thepresence of palladium on carbon in the presence of two equivalents of asuitable salt forming agent, such as sodium bicarbonate (to prepare thedisodium salt of the phosphoramidate product) or potassium bicarbonate(to prepare the dipotassium salt of the product). The product may bepurified by crystallization or by normal or reverse phasechromatography.

As depicted in Scheme 10, treatment of, for example, a triazolone orimidazolone-containing tachykinin antagonist with a suitable base, suchas diisopropylethylamine, 2,6-dimethylpyridine or triethylamine and1-chloroethyl ethyl carbonate in a compatible solvent such as toluene ordichloroethane, followed by heating the mixture at reflux for 12-24 hr,provides the corresponding N-alkylcarbonate product, which may bepurified by flash chromatography.

Similarly, the same substrate may be treated with the functionalizedcarbonate given in Scheme 11 under similar conditions, such as refluxingin toluene in the presence of diisopropylethylamine,2,6-dimethylpyridine or triethylamine to provide the N-Boc protectedintermediate. Cleavage of the Boc group, for example withtrifluoroacetic acid in methylene chloride or with hydrogen chloride inethyl acetate provides the corresponding salt of the prodrug product.

Generation of the N-oxide prodrug of the aforementioned morpholinetachykinin antagonists may be achieved as shown in Scheme 12 simply bytreatment with an oxygen-transfer agent, such as a peracid, such as3-chloroperoxybenzoic acid or trifluoromethylperacetic acid, or withhydrogen peroxide or alkyl hydroperoxides such as t-butyl hydroperoxidein the presence of a transition metal catalyst, or with Caro's acid (H₂SO₅).

Compounds containing linking groups between the heterocycle and thephosphoryl group may also be prepared, for example as illustrated inScheme 13 (see S. A. Varia, S. Schuller, K. B. Sloan, and V. J. Stella,J. Pharm. Sci., 73, 1068-1073 (1984)). Treatment of the parent compoundwith an aliphatic aldehyde, for example aqueous formaldehyde, providesthe corresponding hydroxymethyl derivatives, which after conversion tothe chloride with phosphorus trichloride, may be treated with silverdibenzyl phosphate. The resulting protected phosphates may be separatedby conventional means, for example silica gel chromatography. Thepurified products may then be convened to the free phosphoric acids asdepicted in Schemes 14 and 15, by treatment with a reducing agent suchas hydrogen gas in the presence of pallidium on carbon.

The object compounds of Formula I obtained according to the reactions asexplained above may be isolated and purified in a conventional manner,for example, extraction, precipitation, fractional crystallization,recrystallization, chromatography, and the like.

The compounds of the present invention are capable of forming salts withvarious inorganic and organic acids and bases and such salts are alsowithin the scope of this invention. Examples of such acid addition saltsinclude acetate, adipate, benzoate, benzenesulfonate, bisulfate,butyrate, citrate, camphorate, camphorsulfonate, ethanesulfonate,fumarate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, methanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, oxalate, pamoate, persulfate,picrate, pivalate, propionate, succinate, tartrate, tosylate, andundecanoate. Base salts include ammonium salts, alkali metal salts suchas sodium, lithium and potassium salts, alkaline earth metal salts suchas calcium and magnesium salts, salts with organic bases such asdicyclohexylamine salts, N-methyl-D-glucamine, and salts with aminoacids such as arginine, lysine, ornithine and so forth. Also, the basicnitrogen-containing groups may be quaternized with such agents as: loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride,bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl;diamyl sulfates; long chain halides such as decyl, lauryl, myristyl andstearyl chlorides, bromides and iodides; aralkyl halides like benzylbromide and others. The non-toxic physiologically acceptable salts arepreferred, although other salts are also useful, such as in isolating orpurifying the product.

The salts may be formed by conventional means, such as by reacting thefree base form of the product with one or more equivalents of theappropriate acid in a solvent or medium in which the salt is insoluble,or in a solvent such as water which is removed in vacuo or by freezedrying or by exchanging the anions of an existing salt for another anionon a suitable ion exchange resin.

Although the reaction schemes described herein are reasonably general,it will be understood by those skilled in the art of organic synthesisthat one or more functional groups present in a given compound offormula I may render the molecule incompatible with a particularsynthetic sequence. In such a case an alterative route, an altered orderof steps, or a strategy of protection and deprotection may be employed.In all cases the particular reaction conditions, including reagents,solvent, temperature, and time, should be chosen so that they areconsistent with the nature of the functionality present in the molecule.

As one skilled in the art will recognize, Examples 1-93 describe thepreparation of various parent compounds, whereas Examples 94-96 detailthe preparation of specific prodrugs of some of the parent compounds.Accordingly, the methodology presented in Examples 94-96 is readilyadapted without undue experimentation to the preparation of thecompounds of the present invention, including prodrugs of the parentcompounds of Examples 1-93.

The following examples are given for the purpose of illustrating thepresent invention and shall not be construed as being limitations on thescope or spirit of the instant invention.

EXAMPLE 1

(±)-α-Bromo-phenylacetaldehyde, 3,5-bis(trifluoro-methyl)benzyl acetal

A solution of 2.50 g (10.2 mmol) of α-bromophenylacetaldehyde, dimethylacetal, 8.00 g (32.8 mmol) of 3,5-bis(trifluoromethyl)benzyl alcohol and0.50 g (2.6 mmol) of p-toluenesulfonic acid monohydrate in 10 mL oftoluene was stirred under vacuum (35 mmHg) at rt for 3 days. Thereaction mixture was partitioned between 100 mL of ether and 50 mL ofsaturated aqueous sodium bicarbonate solution and the layers wereseparated. The organic layer was washed with 25 mL of saturated aqueoussodium chloride solution, dried over magnesium sulfate, and concentratedin vacuo. Flash chromatography on 200 g of silica gel using 9:1 v/vhexane/methylene chloride as the eluant afforded 5.41 g (81%) of thetitle compound as a solid, mp 79°-82° C.: 1H NMR 4.47 and 4.62 (AB q, 2H, J=12.5), 4.78-4.93 (2 H), 5.09 and 5.21 (AB q, 2 H, J=7.7), 7.31-7.44(m, 7 H), 7.70 (app s, I H), 7.82 (app s, 1 H), 7.84 (app s 2 H);

IR (thin film) 1363, 1278, 1174, 1130, 704, 682. Analysis Calcd for C₂₆H₁₇ BrF₁₂ O₂ : C, 46.76; H, 2.23; Br, 11.64; F, 33.70. Found: C, 46.65;H, 2.56; Br, 11.94; F, 34.06.

EXAMPLE 2

(±)-N-(2-Hydroxyethyl)-phenylglycinal, 3,5-bis-(trifluoromethyl)benzylacetal

A solution of 1.50 g (2.2 mmol) of (±)-α-bromophenylacetaldehyde,3,5-bis(trifluoromethyl)-benzyl acetal (Example 1), 100 mg (0.67 mmol)of sodium iodide and 3 mL of ethanolamine in 6 mL of isopropanol washeated at reflux for 20 h. The solution was cooled and concentrated to˜25% the original volume in vacuo. The concentrated solution waspartitioned between 50 mL of ether and 20 mL of 2N aqueous sodiumhydroxide solution and the layers were separated. The organic layer waswashed with 20 mL of saturated aqueous sodium chloride solution, driedover magnesium sulfate and concentrated in vacuo. Flash chromatographyon 50 g of silica gel using 65:35 v/v ether/hexane as the eluantafforded 1.18 g (83%) of the title compound as an oil: ¹ H NMR 2.66 (brs, 2 H), 2.61 and 2.68 (ddAB q, 2 H, J_(AB) =12.4, J₂.61 =6.8, 6.2,J₂.68 =6.2, 6.2), 3.57 and 3.66 (ddAB q, 2 H, J_(AB) =10.8, J₃.57 =6.2,6.2), J₃.66 =6.8, 6.2), 4.02 (d, 1 H, J=7.0), 4.37 and 4.64 (AB q, 2 H,J=12.5), 4.80 and 4.87 (AB q, 2 H, J=12.8), 4.87 (d, 1 H, J=7.0),7.31-7.40 (7 H), 7.73 (app s, 1 H), 7.81 (app s, 3 H);

IR (neat) 3342, 1456, 1373, 1278, 1173, 1128, 704, 682; FAB-MS650(M+1)⁺. Analysis Calcd for C₂₈ H₂₃ F₁₂ NO₃ : C, 51.78; H, 3.57; N,2.16; F, 35.11. Found: C, 51.80; H, 3.67; N, 2.10; F, 35.41.

EXAMPLE 3

(±)-N-(2-Hydroxyethyl)-N-(prop-2-enyl)-phenyl-glycinal,3,5-bis(trifluoromethyl)benzyl acetal

A mixture of 1.45 g (2.2 mmol) of (±)-N-(2-hydroxyethyl)-phenylglycinal,3,5-bis-(trifluoromethyl)benzyl acetal (Example 2), 1.0 g (7.2 mmol) ofpotassium carbonate, 3.0 mL (35.0 mmol) of allyl bromide and 15 mL ofethanol was stirred at 60 ° C. for 20 h. The mixture was cooled,partitioned between 100 mL of ether and 25 mL of water and the layerswere separated. The organic layer was dried over magnesium sulfate. Theaqueous layer was extracted with 100 mL of ether; the ether extract wasdried and combined with the original organic layer. The combined organiclayers were concentrated in vacuo. Flash chromatography on 50 g ofsilica gel using 4:1 v/v hexane/ether as the eluant afforded 1.36 g(88%) of the title compound, as an oil: ¹ H NMR 2.40 (dt, 1 H, J=13.2,2.8), 2.93-3.08 (3 H), 3.30 (ddt, I H, J=12.0, 2.8, 1.6), 3.54 (br m, 2H), 3.65 (dt, 1 H, J=10.0, 2.8), 4.23 (d, I H, J=8.4), 4.52 and 4.58 (ABq, 2 H, J=12.4), 4.85 and 4.95 (AB q, 2 H, J=12.4), 5.25 (d, 1 H,J=9.6), 5.28 (d, 1 H, J=16.4), 5.39 (d, 1 H, J=8.4), 5.81 (m, 1 H),7.24-7.40 (7 H), 7.68 (s 1 H), 7.83 (s, I H), 7.86 (s, 2 H);

IR (neat) 3457, 1362, 1278, 1174, 1132, 1056, 759, 705,682; FAB-MS690(M+1)⁺. Analysis Calcd for C₃₁ H₂₇ F₁₂ NO₃ : C, 53.99; H, 3.95; N,2.03; F, 33.07. Found: C, 54.11; H, 4.08; N, 1.78; F, 32.75.

EXAMPLE 4

(±)-2,(3,5-Bis(trifluoromethyl)benzyloxy)-3-phenyl-morpholine

Step A:

A solution of 850 mg(1.2 mmol) of(±)-N-(2-hydroxyethyl)-N-(prop-2-enyl)-phenyl-glycinal,3,5-bis(trifluoromethyl)benzyl acetal (Example 3) and 700 mg (3.7 mmol)of p-toluenesulfonic acid monohydrate in 15 mL of toluene was heated atreflux for 1.5 h. The reaction mixture was cooled and partitionedbetween 100 mL of ether and 25 mL of saturated aqueous sodiumbicarbonate solution. The layers were separated; the organic layer waswashed with 25 ml, of saturated aqueous sodium chloride solution, driedover magnesium sulfate, and concentrated in vacuo. Flash chromatographyon 30 g of silica gel using 50:1 v/v hexane/ether as the eluant afforded426 mg (78%) of the N-allyl morpholines which were used in the next stepwithout further purification.

Step B:

A 50 mL 2-necked flask, equipped with a stopper and a short pathdistillation apparatus, was charged with a solution of the N-allylmorpholines (Example 4, Step A) (540 mg, 1.2 mmol)) and 80 mg (0.09mmol) tris(triphenylphosphine)rhodium chloride (Wilkinson's catalyst) in25 mL of 4:1 v/v acetonitrile/water. The reaction mixture was heated toboiling and solvent was allowed to distill from the reaction mixture.The volume of the reaction mixture was maintained between 10 and 20 mLby adding solvent through the stoppered inlet. After 1 h and 4 h, thereaction was treated with additional 80 mg portions of the Wilkinson'scatalyst. After 6 h, the reaction mixture cooled and partitioned between75 mL of ether and 50 mL of water. The layers were separated and theorganic layer was dried over magnesium sulfate. The aqueous layer wasextracted with 75 mL of ether; the extract was dried and combined withthe original organic layer. The combined organic layers wereconcentrated in vacuo. Flash chromatography on 35 g of silica gel using1:1 v/v ether/hexane as the eluant afforded 200 mg of trans-isomer and130 mg of a mixture of cis- and trans-isomers (68% total).Chromatography of the mixture on 8 g of silica gel using 4:1 v/vhexane/ether as the eluant afforded 64 mg of cis and 57 mg of a mixtureof the cis- and trans-isomers of the title compound. For trans: ¹ H NMR2.03 (br s, 1 H), 2.94 (ddd, 1 H, J=11.0, 2.5, 2.5), 3.08 (dt, 1 H,J=11.0, 3.2), 3.71 (d, 1 H, J=7.0), 3.83 (dt, 1 H, J=11.2, 2.8), 4.05(ddd, 1 H, J=11.2, 3.2, 3.2), 4.43 (d, 1 H, J=7.0), 4.53 and 4.88 (AB q,2 H, J=13.3), 7.26-7.45 (7 H), 7.70 (s, 1 H);

IR (neat) 3333, 2859, 1456, 1374, 1278, 1173, 1131, 1082, 757,702, 682;FAB-MS 406(M+1)⁺. Analysis Calcd for C₁₉ H₁₇ F₆ NO₂ : C, 56.30; H, 4.23;N, 3.46; F, 28.12. Found: C, 56.39; H, 4.28; N, 3.36; F, 28.32. For cis:¹ H NMR 2.10 (br s, 1 H), 3.13 (dd, 1 H, J=12.4, 3.0), 3.26 (dt, 1 H,J=12.4, 3.6), 3.65 (dd, 1 H, J=11.6, 3.6), 4.07 (dt, 1 H, J=11.6, 3.0),4.14 (d, 1 H, J=2.4), 4.52 and 4.82 (AB q, 2 H, J=13.6), 4.76 (d, 1 H,J=2.4), 7.30-7.42 (6 H), 7.70 (s, 1 H), FAB-MS 406(M+1)⁺.

EXAMPLE 5

(±)-2-(3,5-Bis(trifluoromethyl)benzyloxy)-3-phenyl-4-methylcarboxamidomorpholine

A solution of 105 mg (0.26 mmol) of the trans-isomer of(±)-2-(3,5-bis(trifluoromethyl)benzyloxy)-3-phenyl-morpholine (Example4) and 0.09 mL (0.50 mmol) of N,N-diisopropylethylamine in 3 mL ofacetonitrile was treated with 90 mg (0.50 mmol) of iodoacetamide and theresulting solution was stirred at n for 16 h. The solution wasconcentrated in vacuo and the residue was partitioned between 20 mL ofethyl acetate and 10 mL of 0.5 N aqueous potassium hydrogen sulfatesolution. The layers were separated; the organic layer was washed with10 mL of 5% aqueous sodium thiosulfate solution, 10 mL of saturatedaqueous sodium bicarbonate solution, 10 mL of saturated aqueous sodiumchloride solution, dried over magnesium sulfate and concentrated invacuo. Flash chromatography on 5 g of silica gel using 2:1 v/v ethylacetate/hexane as the eluant afforded 99 mg (82%) of the trans-isomer ofthe title compound as an oil: ¹ H NMR 2.56 (dt, I H, J=3.2, 11.6), 2.67and 3.16 (AB q, 2 H, J=16.4), 2.96 (dt, 1 H, J=12.0, 1.6), 3.30 (d, 1 H,J=7.0), 3.86 (dt, 1 H, J=3.2, 12.0), 4.08 (ddt, 1 H, J=11.6, 3.2, 1.6),4.48 and 4.84 (AB q, 2 H, J=13.2), 4.49 (d, 1 H, J=7.0), 5.98 (br s, 1H), 6.83 (br s, 1 H), 7.33 (app s, 7 H), 7.70 (s, 1 H):

IR (neat) 3445, 2838, 1682, 1278, 1173, 1132, 760, 704, 682; FAB-MS 463(M+1)⁺. Analysis Calcd for C₂₁ H₂₀ F₆ NO₃ : C, 54.54; H, 4.36; N, 6.06;F, 24.65. Found: C, 54.54; H, 4.52; N, 5.61; F, 24.45.

A similar experiment was carded out on 40 mg (0.99 mmol) of thecis-isomer of(±)-2-(3,5-bis-(trifluoromethyl)benzyloxy)-3-phenyl-morpholine (Example4) using 0.035 mL (0.2 mmol) of N,N-diisopropylethylamine and 37 mg (0.2mmol) of iodoacetamide in the reaction. Work-up and flash chromatographyafforded 30 mg (65%) of the cis-isomer of the title compound as an oil:¹ H NMR 2.54 and 3.04 (AB q, 2 H, J=16.8), 2.63 (dr, 1 H, J=3.6, 12.0),3.04 (d, 1 H, J=11.6), 3.65 (d, I H, J=2.8), 3.71 (ddt, 1 H, J=11.6,3.2, 1.2), 4.21 (dt, I H, J=11.6, 2.4), 4.44 and 4.89 (AB q, 2 H,J=13.6), 4.71 (d, 1 H, J=2.8), 5.86 (br s, 1 H), 7.15 (br s, 1 H),7.27-7.45 (7 H), 7.73 (s, 1 H); FAB-MS 463(M+1)⁺.

EXAMPLE 6

(±)-2-(3,5-Bis(trifluoromethyl)benzyloxy)-3-phenyl-4-(methoxycarbonylmethyl)morpholine

A solution of 150 mg (0.37 mmol) of the trans-isomer of(±)-2-(3,5-bis(trifluoromethyl)benzyloxy)-3-phenyl morpholine (Example4) and 0.18 mL (1.00 mmol) of N,N-diisopropyl-ethyl- amine in 2 mL ofacetonitrile was treated with 0.095 mL (1.00 mmol) of methylbromoacetate and the resulting solution was stirred at rt for 20 h. Thesolution was concentrated in vacuo and the residue was partitionedbetween 20 mL of ethyl acetate and 5 mL of 0.5N aqueous potassiumhydrogen sulfate solution. The layers were separated; the organic layerwas washed with 10 mL of saturated aqueous sodium chloride solution,dried over magnesium sulfate and concentrated in vacuo. Flashchromatography on 10 g of silica gel using 4:1 v/v hexanes/ether as theeluant afforded 164 mg (93%) of the trans-isomer of the title compoundas an oil: ¹ H NMR 2.79 (dr, 1 H, J=3.2, 11.2), 2.93 (dt, 1 H, J=11.2,1.6), 3.52 (d, 1 H, J=7.2), 3.63 (s, 3 H), 3.92 (dt, 1 H, J=2.8, 11.6),4.04 (ddd, 1 H, J=11.6, 3.2, 1.6), 4.45 and 4.84 (AB q, 2 H, J=13.2),4.46 (d, 1 H, J=7.2), 7.31-7.38 (m, 6 H), 7.68 (s, 1 H);

IR (neat) 2861, 1744, 1455, 1375, 1346, 1278, 1170, 887,759,704, 682;FAB-MS 478(M+1)⁺. Analysis Calcd for C₂₂ H₂₁ F₆ NO₄ : C, 55.35; H, 4.43;N, 2.93; F, 23.88. Found: C, 55.74; H, 4.50; N, 2.79; F, 24.01.

EXAMPLE 7

N-Methoxy-N-methyl-(N-t-butoxycarbonyl)-phenylglycinamide

A solution of 20.0 g (79.7 mmol) of (N-t-butoxycarbonyl)phenylglycine in150 mL of ethyl acetate at -10° C. was treated with 8.8 mL (79.7 mmol)of 4-methyl-morpholine. Isobutylchloroformate (10.3 mL, 79.7 mmol) wasadded dropwise over 10 minutes maintaining the temperature at -10° C.;the resulting suspension was stirred cold for 15 min. The mixture wastreated with 11.6 g (119.0 mmol) of N,O-Dimethyl-hydroxylamine •HCl. Asecond portion of 4-methyl-morpholine (13.0 mL, 119.0 mmol) was addedand the reaction was stirred at -10° C. for 15 min and at 25° C. for 2h. The reaction mixture was partitioned between 100 mL of ethyl acetateand 100 mL of 10% aqueous citric acid solution and the layers wereseparated. The organic layer was washed with 100 mL of saturated aqueoussodium bicarbonate solution, 100 mL of saturated aqueous ammoniumchloride solution, dried over magnesium sulfate and concentrated invacuo. Crystallization from hexanes at -20° C. for 72 h afforded 8.0 g(34%) of the title compound as a solid: ¹ H NMR 1.40 (s, 9 H), 3.20 (s,3 H), 3.40 (s, 3 H), 5.80 (m, 2 H), 7.40 (m, 5 H).

EXAMPLE 8

Diethyl (2-oxo-butoxycarbamido-3-phenyl)-propylphosphonate

A solution of 7.45 mL (51.0 mmol) of diethyl methylphosphonate intetrahydrofuran at -78° C. was treated with 31.8 mL (51.0 mmol) of 1.6 Mn-butyllithium in hexanes solution and the resulting mixture was stirredcold for 30 min. A solution of 4.0 g (14.0 mmol) ofN-methoxy-N-methyl-(N-t-butoxycarbonyl)phenylglycinamide (Example 7) in20 mL of tetrahydrofuran was added and the reaction was stirred at -78°C. for 15 min and at 25° C. for 15 min. The reaction was quenched with150 mL of saturated aqueous ammonium chloride solution, diluted with 300mL of ethyl acetate, and the layers were separated. The organic layerwas dried over magnesium sulfate and concentrated in vacuo. Flashchromatography on silica gel using 7:3 v/v then 4:1 v/v ethylacetate/hexanes as the eluant afforded 4.8 g (92%) of the title compoundas an oil: ¹ H NMR 1.20-1.42 (15 H), 2.84 (dd, 1 H), 3.20 (dd, 1 H),4.00-4.20 (m, 4 H), 5.50 (d, 1 H), 5.94 (br s, 1 H), 7.32 (m, 5 H).

EXAMPLE 9

N-t-Butoxycarbonyl-1-phenyl-2-oxo-4-(3,5-bis(tri-fluoromethyl)-phenyl)-but-3-enamine

A solution of 4.80 g (12.5 mmol) of diethyl(2-oxo-3-t-butoxycarbamido-3-phenyl)propylphosphonate (Example 8) in 20mL of THF was added dropwise to a suspension of 1.05 g (26.3 mmol, 60%dispersion in mineral oil) of sodium hydride in 30 mL of tetrahydrofuranat 0° C. After 15 min, 2.06 mL (12.5 mmol) of3,5-bis(trifluoromethyl)benzaldehyde was slowly added and the resultingmixture was stirred cold for 15 min. The reaction was quenched with 50mL of saturated aqueous ammonium chloride solution, diluted with 50 mLof ethyl acetate, and the layers were separated. The organic layer wasdried over magnesium sulfate and concentrated in vacuo. Flashchromatography on silica gel using 19:1 v/v, then 9:1 v/v ethylacetate/petroleum ether as the eluant afforded 3.30 g (56%) of the titlecompound as a solid: ¹ H NMR 1.40 (s, 9 H), 5.38 (d, 1 H), 5.90 (d, 1H), 6.80 (d, 1 H), 7.39 (m, 5 H), 7.70 (s, 1 H), 7.84 (s, 3 H).

EXAMPLE 10

1-Phenyl-2-hydroxy-4-(3,5-bis(trifluoromethyl)phenyl)-but-3-enamine•HCl

A solution of 1.00 g (2.1 mmol) ofN-t-butoxycarbonyl-1-phenyl-2-oxo-4-(3,5-bis(trifluoromethyl)phenyl)-but-3-enamine(Example 8) in 30 mL of methanol at 0° C. was treated with 241 mg (6.3mmol) of sodium borohydride. After 30 min, the reaction was quenchedwith 50 mL of water and concentrated in vacuo to remove the methanol.The mixture was partitioned between 100 mL of ethyl acetate and 50 mL ofwater and the layers were separated. The organic layer was dried overmagnesium sulfate and concentrated in vacuo. Crystallization fromether/hexanes afforded 680 mg (68%) of the title compound as a 5:1mixture of diastereomers (each protected as the t-butylcarbamate): ¹ HNMR (* indicates the resonances of the minor diastereomer) 1.40 (s, 9H), 4.60 (dd, 1 H), 4.90 (br s, 1 H), 5.20 (br d, 1 H), 6.30 (dd, 1 tt),6.40 (dd. I H*), 6.70 (dd, 1 H), 6.80 (dd, 1 H*), 7.40 (m, 5 H), 7.80(m, 3 H).

A solution of BOC-protected title compound in methanol (saturated withHCl) was allowed to stand for 72 h. The solution was concentrated invacuo. Recrystallization of the resulting solid from ether/hexaneafforded 500 mg (80%) of the title compound •HCl as a solid: ¹ H NMR4.20 (br s, 1 H), 4.40 (d, 1 H), 6.20 (dd, 1 H), 6.60 (dd, 1 H), 7.30 (m5 H), 7.80 (m, 3 H).

The title compound •HCl was dissolved in ethyl acetate and 1N aqueoussodium hydroxide solution. The layers were separated; the organic layerwas dried over magnesium sulfate and concentrated in vacuo to afford thetitle compound as the free base.

EXAMPLE 11

2-(2-(3,5-Bis(trifluoromethyl)phenyl)ethenyl)-3-phenyl-5-oxo-morpholine

A solution of 1.95 g (5.2 mmol) of1-phenyl-2-hydroxy-4-(3,5-bis(trifluoromethyl)phenyl)-but-3-enamine(Example 10) in 20 mL of toluene was added to a suspension of 250 mg(6.2 mmol, 60% dispersion in mineral oil) of sodium hydride in 30 mL oftoluene and the resulting mixture was stirred at rt for 15 min. Asolution of 0.60 mL (1.15 mol) of ethyl chloroacetate in 5 mL of toluenewas slowly added and the resulting mixture was heated at reflux for 3 h.The reaction was cooled, quenched with 50 mL of saturated aqueousammonium chloride solution, diluted with 50 mL of ethyl acetate and thelayers were separated. The organic layer was dried over magnesiumsulfate and concentrated in vacuo. Flash chromatography using ethylacetate/hexanes (4:1 v/v, then 3:1 v/v, then 1:1 v/v) then ethyl acetateas the eluant afforded 300 mg of trans-title compound and 800 mg ofcis-title compound (55% total), both as solids. For the cis-isomer: 1HNMR 1.20-1.40 (m, I H), 1.50-1.62 (m, 1 H), 2.60-2.98 (m, 2 H), 3.86(dt, I H), 4.24 (d, 1 H), 4.34 (dd, 1 H), 4.45 (d, 1 H), 6.40 (br s, 1H), 7.24 (m, 2 H), 7.40 (m, 3 H), 7.50 (s, 2 H), 7.70 (s, 1 H).

EXAMPLE 12

3-Phenyl-2-(2-(3,5 :bis(trifluoromethyl)pheyyl)ethyl)morpholine

A solution of 95 mg (0.23 mmol) of2-(2-(3,5-bis(trifluoromethyl)phenyl)ethenyl)-3-phenyl-5-oxo-morpholine(Example 11 ) in 10 mL of 1:1 v/v ethanol/ethyl acetate was treated with10 mg of palladium hydroxide and the resulting mixture was stirred underan atmosphere of hydrogen for 2 h. The catalyst was filtered and thefiltrate was concentrated in vacuo. The crude product was used directlywithout further purification.

A solution of 65 mg of the crude morpholinone was dissolved in 10 mL oftetrahydrofuran was treated with 0.84 mL of 1M boraneotetrahydrofurancomplex solution in tetrahydrofuran and the resulting solution washeated at reflux for 16 h. The reaction was quenched by adding 10 mL ofmethanol and 70 mg of potassium carbonate and heating the resultingmixture at reflux for 3 h. All volatiles were removed in vacuo and theresidue was partitioned between 20 mL of ethyl acetate and 10 mL ofsaturated ammonium chloride solution. The organic layer was separated,dried over sodium carbonate, and concentrated in vacuo. The residue wasdissolved in saturated HCl in methanol and concentrated in vacuo. Theresidue was triturated with ether; the resulting solid was filtered anddried to afford 32 mg (46%) of the title compound .HCl, mp 114°-116° C.:¹ H NMR 1.42 (m, 1 H), 1.66-1.84 (m, 1 H), 2.70-2.94 (m, 2 H), 3.00 (m,1 H), 3.30-3.46 (m, 1 H), 3.80-3.94 (m, 2 H), 4.10 (m, 1 H), 4.20 (d, 1H), 7.40 (m, 3 H), 7.64 (m, 5 H); CI-MS 402(M+1)⁺.

EXAMPLE 13

N-Benzyl-(S)-phenylglycine

A solution of 1.51 g (10.0 mmol) of (S)-phenylglycine in 5 mL of 2Naqueous sodium hydroxide solution was treated with 1.0 mL (10.0 mmol) ofbenzaldehyde and stirred at room temperature for 20 minutes. Thesolution was diluted with 5 mL of methanol, cooled to 0° C., andcarefully treated with 200 mg (5.3 mmol) of sodium borohydride. Thecooling bath was removed and the reaction mixture was stirred at roomtemperature for 1.5 hours. The reaction was diluted with 20 mL of waterand extracted with 2×25 mL of methylene chloride. The aqueous layer wasacidified with concentrated hydrochloric acid to pH 6 and the solid thatprecipitated was filtered, washed with 50 mL of water, 50 mL of 1:1 v/vmethanol/ethyl ether and 50 mL of ether, and dried to afford 1.83 g(76%) of product, mp 230°-232° C.

Analysis Calcd for C₁₅ H₁₅ NO₂ : C, 74.66; H, 6.27; N, 5.81. Found: C,74.17; H, 6.19; N, 5.86.

EXAMPLE 14

3-(S)- Phenyl-4-benzyl-2-morpholinone

A mixture of 4.00 g (16.6 mmol) of N-benzyl-(S)-phenylglycine (fromExample 13), 5.00 g (36.0 mmol) of potassium carbonate, 10.0 mL of1,2-dibromoethane and 25 mL of N,N-dimethylformamide was stirred at 100°C. for 20 hours. The mixture was cooled and partitioned between 200 mLof ethyl ether and 100 mL of water. The layers were separated and theorganic layer was washed with 3×50 mL of water, dried over magnesiumsulfate and concentrated in vacuo. The residue was purified by flashchromatography on 125 g of silica gel eluting with 9:1 v/v, then 4:1 v/vhexanes/ethyl ether to afford 2.41 g (54%) of the product as a solid, mp98°-100° C. Mass Spectrum (FAB): m/Z 268 (M+H, 100%). ¹ H NMR (CDCl₃,200 MHz, ppm): 8 2.54-2.68 (m, 1H), 2.96 (dr, J=12.8, 2.8, 1H), 3.14 (d,J=13.3, 1H), 3.75 (d, J=13.3, 1H), 4.23 (s, 1H), 4.29-4.37 (m, 1H), 4.53(dr, J=3.2, 11.0), 7.20-7.56 (m, 10H).

Analysis Calcd for C₁₇ H₁₇ NO₂ : C, 76.38; H, 6.41; N, 5.24. Found: C,76.06; H, 6.40; N, 5.78.

EXAMPLE 15

2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3,4 S)-phenyl-morpholine

Step A: 3,5-B is(trifluoromethyl)benzyl alcohol,trifluoromethanesulfonate ester

A solution of 1.00 g (4.1 mmole) of 3,5-bis(trifluoromethyl)benzylalcohol and 1.05 g (5.12 mmole) of 2,6-di-t-butyl-4-methylpyridine in 45mL of dry carbon tetrachloride under a nitrogen atmosphere was treatedwith 0.74 mL (4.38 mmole) of trifluoromethanesulfonic anhydride at roomtemperature. A white precipitate formed shortly after the addition ofthe anhydride. After 90 min, the slurry was filtered under nitrogen witha Schlenk filter, and the filtrate was concentrated in vacuo. Theresidue, which was a two-phase oil, was dissolved under nitrogen in 10mL of dry toluene. The resulting clear solution was used immediately inStep B below.

Step B:4-Benzyl-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-morpholine

A solution of 0.500 g (1.87 mmole) ofN-benzyl-3-(S)-phenylmorpholin-2-one (from Example 14) in 10 mL of dryTHF was cooled to -75° C. under nitrogen and was treated dropwise with2.06 mL (2.06 mmole) of a 1M solution of lithiumtri(sec-butyl)-borohydride (L-Selectride®) in THF. After stirring thesolution at -75° C. for 30 min, a solution of3,5-bis(trifluoromethyl)benzyl alcohol, trifluoromethanesulfonate esterin toluene was added by cannula so that the internal temperature wasmaintained below -60° C. The resulting solution was stirred at -75° C.for 1 hr and then between -38° C. and -50° C. for 2 hr. The solution wasthen poured into a mixture of 25 mL of ethyl acetate and 20 mL ofsaturated aqueous sodium bicarbonate, and the layers were separated. Theaqueous phase was extracted with 2×30 mL of ethyl acetate, the combinedorganic layers were dried over sodium sulfate, the mixture was filteredand the filtrate concentrated in vacuo. The residue was purified byflash chromatography on 130 g of silica eluting with 2 L of 100:5hexanes:ethyl acetate to give 0.68 g (73%) of an oil, which by ¹ H NMRis a 20:1 mixture of cis:trans morpholines.

¹ H NMR (CDCl₃, 400 MHz, pprn): δ major (cis) isomer: 2.37 (td, J=12,3.6, 1H), 2.86 (app t, J=13, 2H), 3.57 (d, J=2.6, 1H), 3.63 (dq, J=11.3,1,6, 1H), 3.89 (d, J=13.3, 1H), 4.12 (td, J=11.6, 2.4, 1H), 4.40 (d,J=13.6, 1H), 4.69 (d, J=2.9, 1H), 4.77 (d, J=13.6), 7.2-7.4 (m, 8H),7.43 (s, 2H), 7.55 (br d, 2H), 7.69 (s, 1 H).

Step C:2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-morpholine

A mixture of 0.68 g (1.37 mmole) of4-benzyl-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-morpholineand 280 mg of 10% Pd/C in 36 mL of 97:3 ethanol:water was stirred underone atmosphere of hydrogen for 15 hr. The mixture was filtered throughCelite, the filter cake was washed generously with ethanol, and thefiltrated was concentrated in vacuo. The residue was purified by flashchromatography on 68 g of silica eluting with 1L of 33:67hexanes:diethyl ether, then 1L of 25:75 hexanes: diethyl ether to give0.443 g (80%) of an oil, which by ¹ H NMR was pure cis morpholine.

¹ H NMR (CDCl₃, 400 MHz, ppm): δ 1.8 (br s, 1H), 3.10 (dd, J=12.5, 2.9,1H), 3.24 (td, J=12.2, 3.6, 1H), 3.62 (dd, J=11.3, 2.5, 1H), 4.04 (td,J=11.7, 3, 1H), 4.11 (d, J=2.4, 1H), 4.49 (d, J=13.5, 1H), 4.74 (d,J=2.5, 1H), 4.80 (d, J=13.3, 1H), 7.25-7.40 (m, 5H), 7.40 (s, 2H), 7.68(s, 1H).

Analysis Calcd for C₁₉ H₁₇ F₆ NO₂ : C, 56.30; H, 4.23; N, 3.46: F,28.12. Found: C, 56.20; H, 4.29; N, 3.34; F, 27.94.

EXAMPLE 16

2(R)-(3.5-B is(trifluoromethyl)benzyloxy)-3 (R)-phenyl-morpholine

The title compound was prepared from (R)-phenylglycine employing theprocedures of Examples 13, 14 and 15.

EXAMPLE 17

4-(3-(1,2,4-Triazolo)methyl)-2-(S)-(3,5-bis(trifluoro-methyl)benzyloxy)-3-(S)-phenyl-morpholine

Step A: N-Formyl-2-chloroacetamidrazone

A solution of 5 g (66.2 mmole) of chloroacetonitrile in 30 mL of drymethanol was cooled to 0° C. under nitrogen and was treated with 0.1 g(1.8 mmole) of sodium methoxide. The mixture was allowed to warm to roomtemperature and was stirred for 30 min, and 0.106 mL (1.8 mmole) ofacetic acid was added. To the resulting mixture was then added 3.9 g(64.9 mmole) of formic hydrazide, and the material was stirred for 30min. The reaction mixture was concentrated in vacuo to a solid, and wasused as such in Step B below.

Step B:4-(3-(1,2,4-Triazolo)methyl)-2-(S)-(3,5-bis-(trifluoromethyl)benzyloxy)-3-(S):phenyl-morpholine

A solution of 0.295g (0.73 mmole) of2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-morpholine (fromExample 15) in 10 mL of dry DMF was treated with 0.302g (2.18 mmole) ofanhydrous potassium carbonate and then 0.168g (1.24 mmole) ofN-formyl-2-chloroacetamidrazone (from Example 17, Step A) and thesuspension was stirred at 60° C. for 4 hr. The mixture was then heatedto 120° C. for 4.5 hr. After cooling, the reaction was diluted with 80mL of ethyl acetate and the organic layer was washed with 3×20 mL ofwater. The organic layer was dried over magnesium sulfate, filtered andconcentrated in vacuo. The residue was purified by flash chromatographyon 67 g of silica eluting with 1.5 L of 100:2 methylenechloride:methanol to give 0.22 g of a yellow solid, which wasrecrystallized from hexanes/methylene chloride to give 0.213g (60%) of awhite crystalline solid, mp 134°-135° C. Mass Spectrum (FAB): m/Z 487(M+H, 100%), 259 (35%), 243 (65%), 227 (40%), 174 (25%).

¹ H NMR (CDCl₃, 400 MHz, ppm): δ 2.67 (td, J-11.9, 3.4, 1H), 2.90 (br d,J-11.7, 1H), 3.43 (d, J=15.2, 1H), 3.66 (app dd, J=13, 1.9, 2H), 3.88(d, J=15.1, 1H), 4.17 (td, J=11.7.2.3, 1H), 4.42 (d, J=13.5, 1H), 4.69(d, J-2.6, 1H), 4.77 (d, J=13.5, 1H), 7.30-7.50 (m, 7H), 7.70 (s, 1H),7.94 (s, 1H).

EXAMPLE 18

4-(3-(5-Oxo-1H,4H-1,2,4-triazolo)methyl)-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-morpholine

Step A: N-Methylcarboxy-2-chloroacetamidrazone

A solution of 5.0 g (66.2 mmol) of chloroacetonitrile in 35 mL of drymethanol was cooled to 0° C. and was treated with 0.105 g (1.9 mmol) ofsodium methoxide. The ice-bath was removed and the mixture was allowedto stir at room temperature for 30 minutes. To the reaction was thenadded 0.110 mL (1.9 mmol) of acetic acid and then 5.8 g (64.9 mmol) ofmethyl hydrazinecarboxylate. After stirring 30 minutes at roomtemperature, the suspension was concentrated in vacuo, and placed on thehigh-vac line overnight, to give 10.5 g (98%) of a yellow powder, whichwas employed in Step C below.

¹ H NMR (CD₃ OD, 400 MHz, ppm): δ 3.71 (s, 3H), 4.06 (s, 2H).

Step B:4-(2-(N-Methylcarboxy-acetamidrazono)-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-morpholine

A solution of 2.30 g (5.7 mmol) of2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-morpholine (fromExample 15), 1.13 g (6.8 mmol) of N-methylcarboxy-2-chloroacetamidrazone(from Step A), and 1.50 mL (8.6 mmol) N,N-diisopropylethylamine in 25 mLof acetonitrile was stirred at room temperature for 20 hours. Theproduct, which had precipitated, was filtered, washed with 5 mL of icecold acetonitrile and dried to give 1.83 g of a white solid. Thefiltrate was concentrated in vacuo and the residue was partitionedbetween 50 mL of methylene chloride and 20 mL of water. The layers wereseparated and the organic layer was dried over magnesium sulfate. Theaqueous layer was extracted with 50 mL of methylene chloride; theextract was dried, combined with the original organic layer, and thecombined organics were concentrated in vacuo. The residue was purifiedby flash chromatography on 30 g of silica gel eluting with 50:1:0.1v/v/v methylene chloride/methanol/ammonium hydroxide to afford anadditional 1.09 g of product (96% total). Mass Spectrum (FAB): m/Z 535(M+H, 100%), 462 (16%), 291 (30%), 226 (35%), 173 (25%).

¹ H NMR (CDCl₃, 400 MHz, ppm): δ 2.53 (dt, J=3.5, 12.2, 1H), 2.59 (d,J=14.6, 1H), 2.94 (d, J=11.8, 1H), 3.37 (d, J=14.6, 1H), 3.58 (d,J=2.8), 1H), 3.62-3.72 (m, 1H), 3.75 (s, 3H), 4.16 (dr, J=2.2, 11.8,1H), 4.44 (d, J=13.2, 1H), 4.70 (d, J=2.8, 1H), 4.79 (d, J=13.2), 5.55(br s, 2H), 7.30-7.46 (m, 7H), 7.72 (s, 1H).

Step C:2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-3-(S),phenyl-morpholine

A solution of 2.89 g (5.4 mmol) of4-(2-(N-methylcarboxyacetamidrazono)-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-morpholine (from Step B) in 36 mL of xylenes washeated at reflux for 1.5 hours. The solution was cooled and concentratedin vacuo. The residue was taken up in 50 mL of 3:1 v/v hexanes/ethylacetate which caused crystallization of the product. The product wasfiltered and dried to afford 1.85 g of a solid. Recrystallization of thesolid from 30 mL of 4:1 v/v hexanes/ethyl acetate afforded 1.19 g ofpure product as a white solid, mp=156°-157° C. All of thecrystallization liquors were combined and concentrated in vacuo. Theresidue was purified by flash chromatography on 30 g of silica geleluting with 50:1:0.1 v/v/v methylene chloride/methanol/ammoniumhydroxide to afford an additional 0.69 g of a solid. Threerecrystallizations from 20 mL of 4:1 v/v hexanes/ethyl acetate affordedan additional 0.39 g of pure product as a white solid (58% total). MassSpectrum (FAB): m/Z 503 (M+H), 259 (55%), 226 (40%), 160 (30%).

¹ H NMR (CDCl₃, 400 MHz, ppm): δ 2.57 (app t, J=9.6, 1H), 2.87-2.97 (m,2H), 3.58-3.71 (m, 3H), 4.18 (app t, J=10.4, 1H), 4.46 (d, J=13.6), 4.68(d, J=2.8, 1H), 4.85 (d, J=13.6, 1H), 7.30-7.45 (m, 7H), 7.64 (s, 1H),10.40 (br s, 1H), 10.73 (br s, 1H).

EXAMPLE 19

N-(2-(R)-Hydroxypropyl)-phenylglycinal, 3,5-bis(tri-fluoromethyl)benzylacetal

A mixture of 1.00 g (1.5 mmol) of (±)-a- bromophenylacetaldehyde,3,5-bis(trifluoromethyl)-benzyl acetal (from Example 12), 1.25 mL of(R)-1-amino-2-propanol, 225 mg (1.5 mmol) of sodium iodide, and 3.75 mLof isopropanol was heated at reflux for 20 h. The solution was cooledand concentrated to-25% the original volume in vacuo. The concentratedsolution was partitioned between 50 mL of ether and 20 mL of 2 N aqueoussodium hydroxide solution and the layers were separated. The organiclayer was washed with 20 mL of saturated aqueous sodium chloridesolution, dried over magnesium sulfate and concentrated in vacuo. Flashchromatography on 50 g of silica gel using 65:35 v/v ether/hexane as theeluant afforded 948 mg (95%) of the product as a 1:1 mixture ofinseparable diastereomers. Mass Spectrum (FAB): m/Z 664 (M+H, 25%), 420(20%), 226 (100%).

EXAMPLE 20

N-(2-(S)-Hydroxypropyl)-phenylglycinal, 3,5-bis(tri-fluoromethyl)benzylacetal

Substitution of (S)-1-amino-2-propanol for (R)-1-amino-2-propanol in anexperiment identical to the preceding example afforded 940 mg (95%) ofthe product as a 1:1 mixture of diastereomers.

EXAMPLE 21

N-(2-(R)-Hydroxypropyl)-N-(prop-2-enyl)-(R)-phenyl-glycinal,3,5bis(trifluoromethyl)benzyl acetal andN-(2-(R)-Hydroxypropyl)-N-(prop-2-enyl)-(S)-phenyl-glycinal,3,5-bis(trifluoromethyl)benzyl acetal

A mixture of 933 mg (1.40 mmol) of N-(2-(R)-hydroxy-propyl)-phenylglycinal, 3,5-bis(trifluoromethyl)-benzyl acetal(from Example 19), 1 mL of allyl bromide, 600 mg (4.3 mmol) of potassiumcarbonate, and 5 mL of ethanol was stirred at 60° C. for 20 hours. Themixture was cooled, partitioned between 100 mL of ethyl ether and 25 mLof water and the layers were separated. Flash chromatography on 50 g ofsilica gel using 20:1 v/v ether/hexanes as the eluant afforded 380 mg ofthe (R,R)-amino alcohol (R_(f) =0.72 with 3:2 v/v ether/hexanes as theeluant), 220 mg of the (R ,S)-amino alcohol (R_(f) =0.62 with 3:2 v/vether/hexanes as the eluant), and 285 mg of a mixture of thedisastereomeric amino alcohols. For the (R,R)-amino alcohol: MassSpectrum (FAB): m/Z 704(M+H).

IR (neat) 3476, 2932, 1624, 1454, 1361, 1278, 1175, 1132, 760, 704, 682.

¹ H NMR (CDCl₃, 400 MHz, ppm) 1.12 (d, 3 H, J=6.4), 2.19 and 2.62 (dABq, 2 H, J_(AB) =13.0, J₂.19 =2.3, J₂.62 =10.4), 2.97 (dd, 1 H, J =14.0,8.8), 3.25-3.30 (m, 1 H), 3.76 (s, 1 H), 3.77-3.85 (m, 1 H), 4.21 (d, 1H, J=8.8), 4.49 and 4.55 (AB q, 2 H, J=12.4), 4.86 and 4.92 (AB q, 2 H,J=12.4), 5.27-5.33 (m, 2 H), 5.39 (d, 1 H, J=8.8), 5.79-5.89 (m, 1 H),7.21-7.26 (m, 4 H), 7.35-7.40 (m, 3 H), 7.67 (s, 1 H), 7.81 (s, I H),7.85 (s, 2 H).

Analysis Calcd for C₃₂ H₂₉ F₁₂ NO₃ : C, 54.63; H, 4.15; N, 1.99; F,32.41. Found: C, 54.72; H, 3.94; N, 1.95; F, 32.17.

For the (R,S)-amino alcohol:

Mass Spectrum (FAB): m/Z 704(M+1). IR (neat) 3451, 2931, 1624, 1454,1362, 1277, 704, 683. ¹ H NMR (CDCl₃, 400 MHz, ppm) 1.09 (d, 3 H,J=6.0), 2.48 and 2.71 (dAB q, 2 H, J_(AB) =13.2, J₂.48 =9.6, J₂.62=3.6), 3.05 (dd, 1 H, J =14.4, 6.8), 3.34-3.39 (m, 1 H), 3.35 (s, 1 H),3.76-3.81 (m, 1 H), 4.21 (d, I H, J=8.4), 4.50 and 4.54 (AB q, 2 H,J=12.8), 4.86 and 4.96 (AB q, 2 H, J=12.4), 5.10-5.17 (m, 2 H), 5.39 (d,1 H, J=8.4), 5.68-5.78 (m, 1 tt), 7.23-7.32 (m, 4 H), 7.34-7.39 (m, 3H), 7.69 (s, 1 H), 7.83 (s, 1 H), 7.86 (s, 2 H). Analysis Calcd for C₃₂H₂₉ F₁₂ NO₃ : C, 54.63; H, 4.15; N, 1.99; F, 32.41. Found: C, 54.80; H,4.16; N, 1.90; F, 32.36.

EXAMPLE 22

N-(2-(S)-Hydroxypropyl)-N-(prop-2-enyl)-(S)-phenyl-glycinal,3,5-bis(trifluoromethyl)benzyl acetal andN-(2-(S)-Hydroxypropyl)-N-(prop-2-enyl)-(R)-phenyloglycinal,3,5-bis(trifluoromethyl)benzyl acetal

Substitution of 880 nag (1.33 mmol) ofN-(2-(S)-hydroxypropyl)-phenylglycinal, 3,5-bis(trifluoro-methyl)benzylacetal (Example 20) for the N-(2-(R)-hydroxypropyl)-phenylglycinal,3,5-bis(trifluoromethyl)benzyl acetal in the procedures of the precedingexample afforded 281 mg of the (S,S)-amino alcohol (R_(f) =0.72 with 3:2v/v ether/hexanes as the eluant), 367 mg of the (S,R)-amino alcohol(R_(f) =0.62 with 3:2 v/v ether/hexanes as the eluant), and 197 mg of amixture of the disastereomeric amino alcohols.

EXAMPLE 23

2-(R)-(3,5-B is(trifluoromethyl)benzyloxy)-3-(R)-phenyl-6-(R)-methylmorpholine and2-(S)-(3,5-Bis-(trifluoromethyl)benzyloxy)-3-(R)-phenyl-6-(R)-methylmorpholine Step A:2-(R)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-4-(2-propenyl)-6-(R)-methylmorpholine and2-(S)-(3,5-bis(trifluoro-methyl)-benzyloxy)-3-(R)-phenyl-4-(2-propenyl)-6-(R)-methylmorpholine

A solution of 355 mg (0.50 mmol) ofN-(2-(R)-hydroxy-propyl)-N-(2-propenyl)-(R)-phenylglycinal,3,5-bis(trifluoromethyl)- benzyl acetal (from Example 21) and 285 mg(1.5 mmol) of p-toluensulfonic acid monohydrate in 5 mL of toluene washeated at reflux for 40 min. The solution was cooled and partitionedbetween 40 mL of ether and 15 mL of saturated aqueous sodium bicarbonatesolution. The layers were separated; the organic layer was washed with10 mL of saturated aqueous sodium chloride solution, dried overmagnesium sulfate, and concentrated in vacuo. Flash chromatography on 10g of silica gel using 19:1 v/v hexanes/ether as the eluant afforded 122mg of (2R,3R,6R) product (R_(f) =0.53 with 4:1 v/v hexanes/ether as theeluant) and 62 mg of the (2S, 3R,6R) product (R_(f) =0.23 with 4:1 v/vhexanes/ether as the eluant).

For the (2R,3R,6R) product:

Mass Spectrum (FAB): m/Z 460 (M+H, 65%)

¹ H NMR (CDCl₃, 400 MHz, ppm) 1.35 (d, 3 H, J=6.4), 2.53 and 2.63 (dABq, 2 H, J_(AB) =12.0, J 2.53=3.2. J 2.63=6.8), 2.83 -2.96 (m, 2 H), 3.60(d, 1 H, J=4.0), 4.27-4.32 (m, 1H), 4.57 and 4.84 (AB q, 2 H, J=13.2),4.87 (d, 1 H, J=40), 5.08-5.13 (m, 2 H), 5.76 -5.86 (m. 1 H), 7.31 -7.37(m, 3 H), 7.50-7.52 (m, 2 H), 7.58 (s, 2 H), 7.71 (s, 1 H).

For the (2S,3R,6R) product:

Mass Spectrum (FAB): m/Z 460 (M+H, 65%)

¹ H NMR (CDCl₃, 400 MHz, ppm 1.37 (d. 3 H, J=6.8), 2.48-2.50 (m, 2 H),2.74 and 3.01 (dtAB q, 2 H, J=6.4, 1.2, 12.4) 3.84 (d, 1 H, J =3.6),3.92-3.99 (m, 1 H), 4.70 and 4.93 (A2B q, 2 H, J=13.6), 4.97 (d. 1 H.J=3.6), 5.08-5.14 (m, 2 H) 5.74-5.84 (m, I H), 7.28-7.36 (m, 3 H),7.43-7.46 (m, 2 H), 7.6,4 (s, 2 ti), 7.75 (s, 1 H).

Step B;2-(R)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-6-(R)-methylmorpholine

A solution of 115 mg (0.25 mmol) of the2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-4-(2-propenyl)-6-(R)-methylmorpholine (from Example 23, Step A) and 230 mg (0.25 mmol) oftris(triphenylphosphine)rhodium chloride in 15 mL of 4:1 v/vacetonitrile/water was heated at reflux for 30 min. The reaction wascooled and partitioned between 50 mL of ethyl acetate and 15 mL ofwater. The layers were separated and the organic layer was dried overmagnesium sulfate. The aqueous layer was extracted with 2×25 mL of ethylacetate; the extracts were dried and combined with the original organiclayer. The combined organics were concentrated in vacuo. The residue wasfiltered through a pad of silica gel (˜20 g) using 2:1 v/v ether/hexanesas the solvent. The filtrate was concentrated; flash chromatography on 5g of silica gel using 17:3 v/v hexanes/ether as the eluant afforded 67mg (64%) of2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-6-(R)-methylmorpholine as an oil.

Mass Spectrum (FAB): m/Z 420 (M+H, 90%)

¹ H NMR (CDCl₃, 400 MHz, ppm) 1.21 (d, 3 H, J=6.4), 2.02 (br s, 1 H),2.67 and 2.77 (dAB q, 2 H, J_(AB) =13.2, J₂.67 =8.8, J₂.77 =3.2), 3.89(d, 1 H, J=2.4), 4.07-4.15 (m, 1 H), 4.68 and 4.90 (AB q, 2 H, J=12.8),5.03 (d, 1 H, J=2.4), 7.28-7.38 (m, 3 H), 7.51-7.53 (m, 2 H), 7.77 (s, 2H), 7.79 (s, 1 H).

Step C:2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-6-(R)-methylmorpholine

A similar reaction was carried out using 55 mg (0.12 mmol) of2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-4-(2-propenyl)-6-(R)-methylmorpholine (from Example 23, Step A) and 111 mg (0.12 mmol) oftris(triphenylphosphine)rhodium chloride in 12 mL of 4:1 v/vacetonitrile/water. Flash chromatography on 4 g of silica gel using 50:1v/v methylene chloride/acetonitrile as the eluant afforded 14 mg (28%)of 2-(S)-(3,5-bis(trifluoromethyl)-benzyloxy)-3-(R)-phenyl-6-(R)-methylmorpholine as an oil.

Mass Spectrum (FAB): m/Z 420 (M+H, 90%)

¹ H NMR (CDCl₃, 400 MHz, ppm) 1.39 (d, 3 H, J=6.8), 1.92 (br s, 1 H),2.84 and 2.95 (dAB q, 2 H, J_(AB) =12.8, J₂.84 =6.4, J₂.95 =3.6),3.93-4.00 (m, 1 H), 4.07 (d, 1 H, J=2.8), 4.68 and 4.95 (AB q, 2 H,J=13.2), 4.93 (d, 1 H, J=2.8), 7.28-7.37 (m, 3 H), 7.48-7.52 (m, 2 H),7.55 (s, 2 H), 7.72 (s, 1 H).

EXAMPLE 242-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(S)-methylmorpholine and 2-(R)-(3,5-Bis-(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(S)-methyl morpholine

Substitution of 350 mg ofN-(2-(S)-hydroxy-propyl)-N-(2-propenyl)-(S)-phenylglycinal,3,5-bis-(trifluoromethyl)benzyl acetal (from Example 22) forN-(2-(R)-hydroxypropyl)-N-(2-propenyl)-(R) -phenylglycinal,3,5-bis(trifluoromethyl)benzyl acetal in an experiment similar to thepreceding example afforded 50 mg of2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(S)-methylmorpholine and 14 mg of2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(S)-methylmorpholine.

EXAMPLE 252-(R)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(R)-methylmorpholine and 2-(S)-(3,5-Bis-(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(g)-methyl morpholine Step A:2-(R)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-4-(2-propenyl)-6-(R)-methylmorpholineand2-(S)-(3,5-bis(trifluoro-methyl)-benzyloxy)-3-(S)-phenyl-4-(2-propenyl)-6-(R)-methylmorpholine

The title compounds were prepared in a manner similar to Example 23,Step A. Cyclization of 300 mg (0.43 mmol) N-(2-(R)-hydroxypropyl)-N-(prop-2-enyl)-(S)-phenylglycinal,3,5-bis(trifluoromethyl)benzyl acetal (from Example 23) was effectedusing 246 mg (1.29 mmol) of p-toluenesulfonic acid monohydrate and 5 mLof toluene. Flash chromatography on 8 g of silica gel using 20:1 v/vhexanes/ether as the eluant afforded 149 mg (75%) of the products asinseparable diastereomrs.

Mass Spectrum (FAB): m/Z 460 (M+H, 65%).

Step B:2-(R)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(R)-methylmorpholine and 2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(R)-methyl morpholine

A solution of 150 mg (0.33 mmol) of2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-4-(2-propenyl)-6-(R)-methylmorpholine and2-(S)-(3,5-bis-(trifluoromethyl)-benzyloxy)-3-(S)-phenyl-4-(2-propenyl)-6-(R)-methylmorpholine (from Example 25, Step A) and 318 mg (0.32 mmol) oftris(triphenyl-phosphine)-rhodium chloride in 20 mL of 4:1 v/vacetonitrile/water was heated at reflux for 1 h. Flash chromatography on5 g of silica gel using 9:1 v/v hexanes/ether as the eluant afforded 35mg of the products as a mixture and 26 mg of2-(R)-(3,5-bis-(trifluoromethyl)benzyloxy)-3-(S)-phenyl -6-(R)-methylmorpholine (R_(f) =0.22 with 3:2 v/v hexanes/ether as the eluant).Chromatography of the mixture on 5 g of silica gel using 20:1 v/vafforded 14 mg of 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(R)-methyl morpholine (R_(f) =0.14 with 3:2 v/v hexanes/etheras the eluant) and 17 mg of 2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(R)-methyl morpholine (41% total yield).

For the (2R,3S.6R) product:

Mass Spectrum (FAB): m/Z 420 (M+H, 90%)

¹ H NMR (CDCl₃, 400 Mhz. ppm) 1.30 (d, 3 H, J=6.4), 1.74 (br s, 1 H),2.73 and 2.98 (dAB q, 2 H, J_(AB) =11.6, J₂.73 =10.0, J₂.98 =2.4), 3.65(d, 1 H, J=7.2), 3.89-3.94 (m, 1 H), 4.45 (d, 1 H, J=7.2), 4.53 and 4.90(AB q, 2 H, J=13.2), 7.28-7.38 (m, 3 H), 7.41-7.43 (m, 2 H), 7.45 (s, 2H), 7.70 (s, 1 H).

For the (2S,3S,6R) product:

Mass Spectrum (FAB): m/Z 420 (M+H, 90%)

¹ H NMR (CDCl₃, 400 Mhz. ppm) 1.20 (d, 3 H, J=6.4), 2.04 (br s, 1 H),2.84 and 3.15 (dAB q, 2 H, J_(AB) =12.8, J₂.84 =10.8, J₃.15 =2.8), 4.08(d, 1H, J=2.8), 4.08-4.15 (m, 1 H), 4.53 and 4.80 (AB q, 2 H, J=13.2),4.79 (d, 1 H, J=2.8), 7.28-7.38 (m, 5 H), 7.43 (s, 2 H), 7.70 (s, 1 H).

EXAMPLE 26 2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-6-(S)-methyl morpholine and2-(R)-(3,5-Bis-(trifluoromethyl)benzyloxy)-3-(R) -phenyl-6-(S)-methylmorpholine

Substitution of 250 mg ofN-(2-(S)-hydroxy-propyl)-N-(2-propenyl)-(S)-phenylglycinal,3,5-bis-(trifluoromethyl)benzyl acetal (from Example 22) forN-(2-(R)-hydroxypropyl)-N-(2-propenyl)-(R) -phenyl-glycinal,3,5-bis(trifluoromethyl)benzyl acetal in an experiment similar to thepreceding example afforded 42 mg of 2-(S)-(3,5-bis-(trifluoromethyl)benzyloxy)-3-(R)-phenyl-6-(S)-methyl morpholine and 17mg of2-(S)-(3,5-bis(trifluoro-methyl)benzyloxy)-3-(R)-phenyl-6-(S)-methylmorpholine.

EXAMPLE 272-(R)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(R)-methylmorpholine, 2-(S)-(3,5-Bis-(tri-fluoromethyl)benzyloxy)-3-(S)-phenyl-5-(R)-methyl morpholine, 2-(R or S)-(3,5-Bis(trifluoromethyl)-benzyloxy)-3-(R)-phenyl-5-(R)-methylmorpholine, and 2-(S orR)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-5-(R)-methylmorpholine

Execution of the sequence described in Example 19 substituting(R)-2-amino-l-propanol for (R)-1-amino-2-propanol provided a mixture of55 mg of high R_(f) material and 56 mg of low R_(f) material. The highR_(f) material was processed according to Example 23, Step A above toprovide 10 mg of high R_(f) material(2-(R)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(R)-methylmorpholine and 7 mg of low R_(f) material(2-(S)-(3,5-Bis(trifluoromethyl) -benzyloxy)-3-(S)-phenyl-5-(R)-methylmorpholine. The low R_(f) material (after being combined with anadditional 30 mg of material) was processed according to Example 23,Step A to provide 24 mg of high R_(f) material (2-(R orS)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-5-(R)-methyl-morpholineand 18 mg of low R_(f) material (2-S) orR)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-5-(R)-methylmorpholine.

2-(R)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(R)-methylmorpholine

Mass Spectrum (FAB): m/Z 420 (M+H, 100%), 227 (50%), 192 (75%), 176(65%).

NMR (CDCl₃, 400 MHz, ppm): δ0.98 (d, 3H, J=6.3 Hz), 3.16-3.20 (m, 1H),3.43-3.47 (m, 1H), 3.79 (d, 1H, J=7.5 Hz), 3.91 (dd, 1H, J=3.2 & 11.5Hz), 4.51 (d, 2H, J=13.4 Hz), 4.85 (d, 1 H, J=13.2 Hz), 7.29 -7.45 (m,7H), 7.67 (s, 1H).

2-(S)-(3,5-Bis (trifluoromethyl)benzyloxy)-3 -(S)-phenyl-5-(R)-methylmorpholine

Mass Spectrum (FAB): m/Z 420 (M+H, 48%), 227 (35%), 192 (39%), 176(100%).

NMR (CDCl₃, 400 MHz, ppm): δ1.10 (d, 3H, J=6.4 Hz), 3.23-3.26 (m, 1H),3.56-3.61 (m, 2H), 4.17 (d, 1H, J=2.3 Hz), 4.51 (d, 1H, J=13.7 Hz), 4.71(d, 1H, J=2.4 Hz), 4.78 (d, 1H, J=13.5 Hz), 7.28-7.39 (m, 7H), 7.68 (s,1H).

2-(R or S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-5-(R)-methylmorpholine

Mass Spectrum (FAB): m/Z 281 (35%), 221 (55%), 207 (45%), 192 (40%), 147(100%).

NMR (CDCl₃, 400 MHz, ppm): δ1.13 (d, 3H, J=6.6 Hz), 3.10-3.14 (m, 1H),3.66 (dd, 1 H, J=6.6 & 11.4 Hz), 3.76 (dd, 1H, J=3.5 & 11.2 Hz), 4.04(d, 1H, J=4.0 Hz), 4.61 (d, 1H, J=13.2 Hz), 4.74 (d, 1H, J=3.9 Hz), 4.89(d, 1H, 13.2 Hz), 7.26-7.35 (m, 3H), 7.47-7.49 (m, 2H), 7.64 (s, 1H),7.74 (s, 1H).

2-(R or S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-5-(R)-methylmorpholine

NMR (CDCl₃, 400 MHz, ppm): δ1.36 (d, 3H, J=6.7 Hz), 3.27-3.31 (m, 1H),3.39 (dd, 1 H, J=2.2 & 11.3 Hz), 4.16 (dd, 1 H, J=3.2 & 11.0 Hz), 4.37(d, 1H, J=2.3 Hz), 4.53 (d, 1H, J=13.5 Hz), 4.75 (d, 1H, J=2.5 Hz), 4.81(d, 1H, 13.6 Hz), 7.26-7.35 (m, 3H), 7.26-7.43 (m, 7H), 7.68 (s, 1H).

EXAMPLE 28 2-(R orS)-(3,5-Bis(trifluoromethyl)-benzyloxy)-3-(S)-phenyl-5-(S)-methylmorpholine,2-(S or R)-(3,5-(-Bis-(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(S)-methyl-morpholine, and2-(R)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-5-(S)-methylmorpholine

Execution of the sequence described in Example 19 substituting(S)-2-amino-1-propanol for (R)-1-amino-2-propanol provided a mixture of78 mg of high R_(f) material and 70 mg of low R_(f) material. The highR_(f) material was processed according to Example 23, Step A above toprovide less than 1 mg of high R_(f) material(2-(R)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(S)-methylmorpholine)and 9 mg of low R_(f) material(2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy) -3-(S)-phenyl-5-(S)-methylmorpholine. The low R_(f) material was processed according to Example23, Step A to provide 20 mg of high R_(f) material (2-(R orS)-(3,5-Bis(trifluoromethyl)-benzyloxy)-3-(S)-phenyl-5-(S)-methylmorpholine and 14 mg of low R_(f)material (2-(S or R)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl -5-(S)-methylmorpholine.

2-(R or S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(S)-methylmorpholine

Mass Spectrum (FAB): m/Z 420 (M+H, 60%), 227 (68%), 192 (56%), 176(100%).

NMR (CDCl₃, 400 MHz, ppm): δ1.12 (d, 3H, J=6.6 Hz), 3.09-3.14 (m, 1H),3.65 (dd, 1H, J=6.6 & 11.0 Hz), 3.75 (dd, 1H, J=3.6 & 11.1 Hz), 4.04 (d,1H, J=3.9 Hz), 4.61 (d, 1H, J=13.2 Hz), 4.73 (d, 1H, J=3.9 Hz), 4.89 (d,1H, 13.2 Hz), 7.28-7.35 (m, 3H), 7.47 (d, 2H, 7.0 Hz), 7.64 (s, 1H),7.74 (s, 1H).

2-(S or R)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(S)-methylmorpholine

Mass Spectrum (FAB): m/Z 420 (M+H, 50%), 227 (45%), 192 (40%), 176(100%).

NMR (CDCl₃, 400 MHz, ppm): δ1.36 (d, 3H, J=6.9 Hz), 3.27-3.29 (m, 1 H),3.39 (dd, 1H, J=2.2 & 11.1 Hz), 4.15 (dd, 1H, J=3.3 & 11.1 Hz), 4.37 (d,1H, J=2.5 Hz), 4.52 (d, 1 H, J=13.3 Hz), 4.75 (d, 1H, J=2.4 Hz), 4.81(d, 1H, 13.5 Hz), 7.28-7.43 (m, 7H), 7.68 (s, 1H).

2-(R)-(3,5-Bis (trifluoromethyl)benzyloxy)-3-(R)-phenyl-5-(S)-methylmorpholine

NMR (CDCl₃, 400 MHz, ppm): δ1.10 (d, 3H, J=6.4 Hz), 3.22-3.25 (m, 1H),3.55-3.60 (m, 2H), 4.17 (d, 1 H, J=2.3 Hz), 4.51 (d, 1H, J=13.5 Hz),4.71 (d, 1H, J=2.4 Hz), 4.77 (d, 1H, J=13.6 Hz), 7.28-7.38 (m, 7H), 7.67(s, 1 H).

EXAMPLE 292-(R)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(R)-phenylmorpholine,2-(S)-(3,5-Bis(tri-fluoromethyl)benzyloxy)-3-(S)-phenyl-5-(R)-phenyl-morpholine, and 2-(R or S)-(3,5-Bis(trifluoro-methyl)-benzyloxy)-3-(R).-phenyl-5-(R)-phenylmorpholine

Execution of the sequence described in Example 19 substituting(R)-2-amino-2-phenylethanol for (R)-1-amino-2-propanol provided amixture of 62 mg of high R_(f) material and 52 mg of low R_(f) material.The high R_(f) material was processed according to Example 23, Step Aabove to provide 16 mg of high R_(f) material(2-(R)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(R)-phenylmorpholine and 4 mg of low R_(f) material(2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(R)-phenylmorpholine. The low R_(f) material wasprocessed according to Example 23, Step A to provide 4 mg of product(2-(R orS)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-5-(R)-phenylmorpholine

2-(R)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(R)-phenylmorpholine

NMR (CDCl₃, 400 MHz, ppm): δ3.62 (t, 1H, J=10.7 & 21.5 Hz), 3.93 (d, 1H,J=7.4 Hz), 3.99 (dd, 1H, J=3.1 & 11.2 Hz), 4.18 (dd, 1H, J=3.0 & 10.2Hz), 4.46 (d, 1H, J=7.4 Hz), 4.53 (d, 1 H, J=13.5 Hz), 4.89 (d, 1 H,J=13.3 Hz), 7.28-7.55 (m, 12H), 7.69 (s, 1H).

2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(R)-phenylmorpholine

NMR (CDCl₃, 400 MHz, ppm): δ3.67 (dd, 1H, J=3.5 & 11.0 Hz), 3.89 (d, 1H,J=10.8 & 21.6 Hz), 4.25 (dd, 1 H, J=3.3 & 11.0 Hz), 4.34 (d, 1H, J=2.2Hz), 4.52 (d, 1H, J=13.8 Hz), 4.78-4.87 (m, 2H), 7.28 -7.51 (m, 12H),7.69 (s, 1H).

2-(R orS)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-5-(R)-phenylmorpholine

NMR (CDCl₃, 400 MHz, ppm): δ4.10-4.25 (m, 2H), 4.30-4.38 (m, 1H),4.48-4.54 (m, 1H), 4.59-4.66 (m, 1H), 4.86-5.00 (m, 2H), 7.25 -7.74 (m,13H).

EXAMPLE 30 2-(S)-(3,5 -Bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-5-(S)-phenylmorpholine,2-(R)-(3,5-Bis(tri-fluoromethyl)benzyloxy)-3-(R)-phenyl-5-(S)-phenyl-morpholine, 2-(R orS)-(3,5-Bis-(trifluoromethyl)-benzyloxy)-3-(S)-phenyl-5-(S)-phenyl-morpholine,and 2-(R orS)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(S)-phenylmorpholine

Execution of the sequence described in Example 19 substituting(S)-2-amino-2-phenylethanol for (R)-1-amino-2-propanol provided amixture of 75 mg of high R_(f) material and 64 mg of low R_(f) material.The high R_(f) material was processed according to Example 23, Step Aabove to provide 23 mg of high R_(f) material(2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-5-(S)-phenylmorpholineL-740, 930!) and 7 mg of low R_(f) material (2-(R)-(3,5-Bis(trifluoro-methyl)benzyloxy)-3-(R)-phenyl-5-(S)-phenylmorpholine. The low R_(f)material was processed according to Example 23, Step A to provide 26 mgof higher R_(f) material (2-(R or S)-(3,5-Bis(trifluoromethyl)benzyl-oxy)-3-(S)-phenyl-5-(S)-phenylmorpholine and 6 mg of lower R_(f)material (2-(R or S)-(3,5-Bis(trifluoro-methyl)benzyloxy)-3-(S)-phenyl-5-(S)-phenylmorpholine.

2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-5-(S)-phenylmorpholine

NMR (CDCl₃, 400 MHz, ppm): δ3.60-3.74 (m, 1H), 3.94 (d, 1H, J=7.6 Hz),4.00 (dd, 1H, J=3.2 & 11.3 Hz), 4.18-4.21 (m, 1H), 4.50-4.55 (m, 2H,),4.89 (m, 1H), 7.26-7.55 (m, 12H), 7.69 (s, 1 H).

2-(R)-(3,5 -Bis (tri fluoromethyl)benzyloxy)-3-(R)-phenyl-5-(S)-phenylmorpholine

NMR (CDCl₃, 400 MHz, ppm): δ3.68 (dd, 1H, J=3.0 & 11.0 Hz), 3.88-3.94(m, 1H), 4.26-4.30 (m, 1H), 4.36 (s, 1H), 4.52 (d, 1H, J=13.5 Hz),4.77-4.86 (m, 2H), 7.27-7.51 (m, 12H), 7.69 (s, 1H).

2-(R orS)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(S)-phenylmorpholine

NMR (CDCl₃, 400 MHz, ppm): δ3.93-3.95 (m, 1H), 4.06-4.21 (m, 2H),4.38-4.42 (m, 1H), 4.59-4.68 (m, 2H), 4.83-4.94 (m, 2H), 7.25 -7.81 (m.13H).

2-(R orS)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(S)-phenylmorpholine

NMR (CDCl₃, 400 MHz, ppm): δ3.43-3.59 (m, 2H), 3.82 (d, 1H, J=7.2 Hz),4.25 (d, 1H, J=12.5 Hz), 4.52-4.63 (m, 3H), 4.80-4.90 (br s, 1H),7.11-7.81 (m, 13H).

EXAMPLE 312-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-6-(R)-methyl-3-(S)-phenyl-4-(3-(1,2,4-triazolo)-methyl)-morpholine

According to the procedure given in Example 17, Step B, 98 mg (0.24mmole) of2-(S)-(3,5-bis-(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(R)-methylmorpholine (from Example 25 above), 38 mg (0.28 mmole) ofN-fomryl-2-chloroacetamidrazone (from Example 17, Step A above) and 97mg (0.7 mmole) of anhydrous potassium carbonate gave, after flashchromatography on 28 g of silica eluting with 1 L of 100:4:0.5 methylenechloride:methanol: ammonia water, a light yellow solid which afterrecrystallization from hexanes/methylene chloride provided 77 mg (66%)of 2-(S)-(3,5-bis(trifluoromethyl)-benzyloxy)-6-(R)-methyl-3-(S)-phenyl-4-(3-(1,2,4-triazolo)-methyl)morpholineas a white powder.

NMR (CDCl₃, 400 MHz, ppm): δ1.17 (d, J=6.3, 3H), 2.29 (t, J=11.1, 1H),2.92 (d, J=11.1, 1H), 3.42 (d, J=15.3, 1H), 3.58 (s, 1H), 3.88 (d,J=15.4, 1H), 4.20-4.33 (m, 1 H), 4.43 (d, 13.5, 1H), 4.71 (d, J=2.4,1H), 4.74 (d, J=13.3, 1H), 7.30-7.55 (m, 7H), 7.69 (s, 1H), 7.95 (s, 1H).

EXAMPLE 32 2-(S)-(3,5 -Bis (trifluoromethyl)benzyloxy)-6-(R)-methyl-4-(3-(5-oxo -1H,4H-1,2,4-triazolo)-methyl)-3:(S),phenylmorpholine

A mixture of 96 mg (0.23 mmole) of 2-(S)-(3,5-bis-(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(R)-methyl morpholine (fromExample 25 above), 46 mg (0.28 mmole) ofN-methylcarboxy-2-chloroacetamidrazone and 95 mg (0.69 mmole) ofanhydrous potassium carbonate in 3 mL of dry DMF was stirred at roomtemperature for 20 min, at 60° C. for 90 min and then at 120° C. for 2hr. The mixture was cooled to room temperature, taken up in 15 mL ofethyl acetate and was washed with 3×10 mL of water. The combined aqueouslayers were back-extracted with 10 mL of ethyl acetate, the combinedorganic layers were washed with 10 mL of brine, dried over sodiumsulfate, filtered and concentrated in vacuo. The residue was purified byflash chromatography on 28 g of silica eluting with 1L of 100:4methylene chloride: methanol to give 65 mg (55%) of2-(S)-(3,5-bis(trifluoro-methyl)benzyl-oxy)-6-(R)-methyl-4-(3-(5-oxo-1H,4 H-1,2,4-triazolo)-methyl)-3-(S)-phenylmorpholine as a light yellow powder.

NMR (CDCl₃, 400 MHz, ppm): δ1.18 (d, J=6.2, 3H), 2.15 (t, J=11.1, 1H),2.89 (d, J=14, 2H), 3.49 (d, J=2.2, 1H), 3.61 (d, J=14.4, 1H), 4.20-4.30(m, 1 H), 4.45 (d, J=13.6, 1 H), 4.67 (d, J=2.5, 1H), 4.79 (d, J=13.5,1H), 7.25-7.50 (m, 7H), 7.62 (s, 1H), 10.07 (s, 1 H), 10.35 (s, 1 H).

EXAMPLE 332-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(R)-phenylmorpholine Step A:4-Benzyl-2-(S)-hydroxy-3-(R)-phenylmorpholine

A solution of 3.72 g {13.9 mmol) of 4-benzyl-3-(R)-phenyl-2-morpholinone, prepared from (R)-phenyl-glycine as described inExample 14, in 28 mL of CH₂ Cl₂ was cooled in a -78° C. bath under a N₂atmosphere and 14 mL of a 1.5 M solution of DIBAL-H (21 mmol) in toluenewere added. After stirring the resulting solution for 0.5 h, it wasallowed to warm to -50° C. and maintained at this temperature for 0.5 h.The reaction mixture was quenched by adding 10 mL of aqueous potassiumsodium tartarate. The mixture was diluted with CH₂ Cl₂ and the layerswere separated. The aqueous layer was extracted 3 times with CH₂ Cl₂.The CH₂ Cl₂ layers were washed with brine, dried over Na₂ SO₄ andfiltered. Concentration of the filtrate furnished 3.32 g (88%) of4-benzyl-2-(S)-hydroxy-3-(R)-phenylmorpholine suitable for use in thenext step.

NMR (CDCl₃) 2.28 (m, 1H), 2.71 (m, 1H), 2.91 (d, J=13 Hz, 1H), 3.09 (d,J=6 Hz, 1H), 3.69 (d, J=13 Hz, 1H), 3.82 (td, J=10 Hz and 2 Hz, 1H),3.91 (d, J=10 Hz, 1H), 4.73 (t, J=6 Hz, 1H), 7.2-7.52 (m, 10 H).

Step B: 4-Benzyl-2-(S)-(3,5-bis(trifluoromethyl)-benzyloxy)-3-(R)-phenylmorpholine

To a suspension of 0.592 g (14.8 mmol) of Nail in 30 mL of dry THF at 0°C. was added 3.32 g (12.3 mmol) of 4-benzyl-2-(S)-hydroxy-3-(R)-phenyl-morpholine prepared in step A. After 15 min 0.915g of tetrabutylammonium iodide (2.47 mmol) and 2.4 mL (13 mmol) of3,5-bis(trifluoromethyl)benzyl bromide were added. The resulting mixturewas stirred at ice-bath temperature for 1 h, then poured into saturatedNaHCO₃ solution and extracted with ethyl acetate (EtOAc). The organiclayers were combined, washed with brine, dried over Na₂ SO₄ andfiltered. The filtrate was concentrated in vacuo and the resiue waschromatographed on a Waters Prep500 HPLC system using 50% EtOAc/Hexaneto isolate 3.6 g (59%) of4-Benzyl-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenylmorpholine.

¹ H NMR (CDCl₃) 2.3 (td, J=11 Hz and 3 Hz, 1H), 2.71 (d, J=11 Hz, 1H),2.90 (d, J=13 Hz, 1H), 3.22 (d, J=7.3 Hz, 1H), 3.75 (m, 2H), 3.93 (m,1H), 4.43 (d, J=13 Hz, 1H), 4.45 (d, J=7.3 Hz, 1H), 4.82 (d, J=13 Hz, 1H), 7.19-7.5 (m, 12H), 7.67 (s, 1H).

Step C: 2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-morpholine

A solution of 3.6 g (7.27 mmol) of4-benzyl-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenylmorpholinein 100 mL of ethanol and 5 mL of water, containing 0.72 g of 10% Pd/Cwas hydrogenated on a Parr apparatus for 36 h. The catalyst was filteredand thoroughly washed with EtOAc. The filtrate was concentrated and theresidue was partitioned between water and EtOAc. The EtOAc layer waswashed with brine, dried over Na₂ SO₄, filtered and concentrated. Theresidue was purified by flash chromatography using a gradient of 10-60%EtOAc/hexane to isolate 2.05 g (70%) of 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenylmorpholine.

¹ H NMR (CDCl₃) 1.92 (br s, 1H), 2.91 (m, 1H), 3.05 (td, J=1 1Hz and 3Hz, 1H), 3.68 (d, J=7 Hz, 1H), 3.81 (td, J=11 Hz and 3 Hz, 1H), 4.01 (m,1H), 4.44 (d, J=7 Hz), 4.5 (d, J=13 Hz, 1H), 4.85 (d, J=13 Hz, 1 H),7.28-7.42 (m, 7H), 7.67 (s, 1H).

EXAMPLE 34 4-(3-(1,2,4-Triazolo)-methyl)-2-(S)-(3,5-bis(trifluoromethyl)-benzyloxy)-3-(R)-phenylmorpholine

The title compound was prepared by the procedure of Example 17, step Bemploying the product of Example 33, step C as a starting material.

¹ H NMR (CDCl₃) 1.75 (br s, 1 H), 2.61 (td, J=12 Hz and 2 Hz, 1H), 2.83(d, J=12 Hz, 1 H), 3.33 (d, J=7 Hz, 1 H), 3.48 (d, J=15 Hz, 1H), 3.78(d, J=15 Hz, 1H), 3.85 (m, 1 H), 3.99 (m, 1H), 4.44 (d, J=13 Hz, 1 H),4.49 (d, J=7Hz, 1 H), 4.81 (d, J=13 Hz, 1H), 7.23-7.45 (m, 7H), 7.67 (s,1H), 7.96 (s, 1H).

EXAMPLE 354-(3-(5-Oxo-1H,4H-1,2,4-triazolo)-methyl)-2-(S)-(3,5-bis-(trifluoro-methyl)benzyloxy)-3-(R)-phenylmorpholine

The title compound was prepared by the procedure of Example 18, steps B& C employing the product of Example 33, step C as a starting material.

EXAMPLE 36 4-(2-(Imidazolo)-methyl)-2-(S)-(3,5-b is(trifluoro-methyl)benzyloxy)-3-(S)-phenylmorpholine

A solution of 101 mg (0.25 mmol) of 2-(S)-(3,5-bis(tri-fluoromethyl)benzyloxy)-3-(S)-phenylmorpholine (Example 15), 98 mg (1.0mmol) of imidazole-2-carboxaldehyde, and 5 drops of glacial acetic acidin 3 ml of methanol was treated with 1.5 ml of 1M sodiumcyanoborohydride solution in THF. After 16 hr, the reaction was quenchedwith 5 ml of saturated aqueous sodium bicarbonate solution andpartitioned between 40 ml of ethyl acetate and 20 ml of water. Theorganic layer was separated, dried over magnesium sulfate, andconcentrated in vacuo. Flash chromatography on 8 g of silica gel using50:1:0.1 methylene chloride/methanol/amonium hydroxide as the eluentafforded 54 mg (44% yield) of the title compound as a white solid.

¹ H NMR (CDCl₃) 2.60 (dt, J=3.2 Hz and 12.4 Hz, 1H), 2.85 (d, J =12.4Hz, 1H), 3.28 (d, J=14.4 Hz, 1H), 3.59 (d, J=2.8 Hz, 1H), 3.66 (dd,J=2.0, 11.6 Hz, 1 H), 3.84 (d, J=14.4 Hz, 1 H), 3.94 (app s, 2H), 4.14(dt, J=2.0, 12.0 Hz, 1H), 4.43 (d, J=13.6 Hz, 1H), 4.71 (d, J=2.8 Hz,1H), 4.78 (d, J=13.6 Hz, 1 H), 6.99 (app s, 2H), 7.25-7.48 (m, 6H), 7.72(s, 1H). Mass spectrum (FAB): m/z 486 (100%, M+H)

EXAMPLE 37 4-(2-(Imidazolo)-methyl)-2-(S)-(3,5-bis(trifluoro-methyl)benzyloxy)-3-(R)-phenylmorpholine

The title compound was prepared by the procedure of Example 36 employingappropriate starting materials.

¹ H NMR (CDCl₃) 2.53 (td, J=11 Hz and 3 Hz, 1H), 2.74 (d, J=12 Hz, 1H),3.23 (d, J=7Hz, 1H), 3.32 (d, J=15 Hz, 1H), 3.66 (d, J=15 Hz, 1H), 3.77(td, J=11 Hz and 2 Hz, 1H), 3.99 (m, 1H), 4.44 (m, 2H), 4.8 (d, J=13 Hz,1H), 6.94 (s, 2H), 7.2-7.45 (m, 7H), 7.67 (s, 1H).

EXAMPLE 38 4-(5-(Imidazolo)-methyl)-2-(S)-(3,5-bis(trifluoro-methyl)benzyloxy)-3-(R)-phenylmorpholine

The title compound was prepared by the procedure of Example 36 employingappropriate starting materials.

¹ H NMR (CDCl₃) 2.47 (td, J=12 Hz and 3 Hz, 1H), 2.83 (d, J=12 Hz, 1H),3.2 (m, 2H), 3.61 (d, J=14 Hz, 1H), 3.79 (td, J=12 Hz and 2 Hz, 1 H),3.96 (m, 1H), 4.44 (m, 2H), 4.80 (d, J=13 Hz, 1H), 6.81 (s, 1H),7.28-7.45 (m, 7H), 7.60 (s, 1H), 7.66 (s, 1H).

EXAMPLE 394-(Aminocarbonylmethyl)-2-(S)-(3,5-bis(trifluoro-methyl)benzyloxy)-3-(R)-phenylmorpholine

The title compound was prepared by the procedure of Example 15 employingappropriate starting materials.

¹ H NMR (CDCl₃) 2.54 (td, J=11 Hz and 2 Hz, 1H), 2.64 (d, J=17 Hz, 1 H),2.93 (d, J 12 Hz, 1H), 3.14 (d, J=17 Hz, 1H), 3.27 (d, J=7 Hz, 1H), 3.83(td, J=11 Hz and 2 Hz. 1 H), 4.05 (m, 1H), 4.46 (m, 2H), 4.81 (d, J=13Hz, 1H), 5.62 (br s, 1 H), 6.80 (br s, 1H), 7.28-7.32 (m, 7H), 7.67 (s,1H).

EXAMPLES 40-434-(3-(1,2,4-Triazolo)-methyl)-2-(3-(tert-butyl)-5-methylbenzyloxy)-3-phenyl-morpholine,4-(3-(5-Oxo-1H,4H-1,2,4-triazolo)-methyl)-2-(3-(tert-butyl)-5-methylbenzyloxy)-3-phenyl-morpholine,4-(2-(Imidazolo)-methyl)-2-(3-(tert-butyl)-5-methyl-benzyloxy)-3-phenylmorpholine,4-(4-(Imidazolo)-methyl)-2-(3-(tert-butyl)-5-methylbenzyloxy)-3-phenyl-morpholine

The title compounds are each prepared by the procedures of Examples 15,17 & 18 employing appropriately substituted starting materials andreagents.

EXAMPLE 44 2-(S)-(3,5-Dichlorobenzyloxy)-3-(S)-phenylmorpholine Step A:3,5-Dichlorobenzyl alcohol, trifluoromethanesulfonate ester

A solution of 6.09 g (34.4 mole) of 3,5-dichlorobenzyl alcohol and 8.48g (41.3 mmole) of 2,6-di-t-butyl-4-methylpyridine in 280 mL of drycarbon tetrachloride under a nitrogen atmosphere was treated with 5.95mL (35.4 mmole) of trifluoromethanesulfonic anhydride at roomtemperature. A white precipitate formed shortly after the addition ofthe anhydride. After 90 min, the slurry was filtered under nitrogen witha Schlenk filter, and the filtrate was concentrated in vacuo. Theresidue, which was a two-phase oil, was dissolved under nitrogen in 60mL of dry toluene. The resulting solution was used immediately in Step Bbelow.

Step B: 4-Benzyl-2-(S)-(3,5-dichlorobenzyloxy)-3-(S)-phenyl -morpholine

A solution of 5.11 g (19.1 mmole) of N-benzyl-3-(S)-phenylmorpholine-2-one (from Example 14) in 100 mL of dry THF wascooled to -75° C. under nitrogen and was treated dropwise with 20.5 mL(20.5 mmole) of a 1M solution of lithium tri(sec-butyl)borohydride(L-Selectride®) in THF. After stirring the solution at -75° C. for 30min, a solution of 3,5-dichlorobenzyl alcohol, trifluoromethanesulfonateester in toluene (from Example 44, Step A) was added by cannula so thatthe internal temperature was maintained below -60° C. The resultingsolution was stirred between -38° C. and -50° C. for 9 hr, and was thentreated with 14 mL of aqueous ammonia and stored at -20° C. for 12hours. The solution was then poured into a mixture of 50 mL of ethylacetate and 100 mL of water, and the layers were separated. The aqueousphase was extracted with 2×100 mL of ethyl acetate, each extract waswashed with brine, the combined organic layers were dried over sodiumsulfate, the mixture was filtered and the filtrate concentrated invacuo. The residue was purified by flash chromatography on 235 g ofsilica eluting with 1.5 L of 100:2 hexanes:ethyl acetate, then 1.5 L of100:3 hexanes:ethyl acetate and then 1.9 L of 100:5 hexanes:ethylacetate to give 4.4 g (54%) of an oil, which by ¹ H NMR is a 8:1 mixtureof cis:trans morpholines.

Mass Spectrum (FAB): m/Z 430,428,426 (M+H, ˜60%), 268 (M-ArCH₂, 100%),252 (M-ArCH₂ O, 75%), 222(20%), 159 (45%).

¹ H NMR (CDCl₃, 400 MHz, ppm): δ major (cis) isomer: 2.32 (td, J=12,3.6, 1H), 2.84 (app t, J=13, 2H), 3.52 (d, J=2.6, 1H), 3.55 (dq, J=11.3,1.6, 1H), 3.91 (d, J=13.3, 1 H), 4.12 (td, J=11.6, 2.4, 1H), 4.29 (d,J=13.6, 1H), 4.59 (d, J=2.9, 1 H), 4.60 (d, J=13.6), 6.70 (s, 2H), 7.13(t, J=1.9, 1H), 7.2-7.6 (m, 8H), 7.53 (br d, 2H).

Step C: 2-(S)-(3,5-Dichlorobenzyloxy)-3-(S)-phenylmorpholine

A solution of 0.33 g (0.77 mmole) of4-benzyl-2-(S)-(3,5-dichlorobenzyloxy)-3-(S)-phenylmorpholine (fromExample 44, Step B) and 0.22 g (1.54 mmole) of 1-chloroethylchloroformate in 4.5 mL of 1,2-dichloroethane was placed in a pressurevial which was lowered into an oil bath which was heated to 110° C.After stirring for 60 hr the solution was cooled and concentrated invacuo. The residue was dissolved in 7 mL of methanol and the resultingsolution was heated at reflux for 30 min. The mixture was cooled andtreated with several drops of concentrated aqueous ammonia and thesolution was concentrated. The residue was partly purified by flashchromatography on 67 g of silica eluting with 1.5 L of 100:1 methylenechloride: methanol, and the rich cuts were purified by flashchormatography on 32 g of silica eluting with 50:50 hexanes: ethylacetate and then 50:50:5 hexanes:ethyl acetate:methanol to give 0.051 g(20%)of an oil, which by ¹ H NMR was pure cis morpholine.

Mass Spectrum (FAB): m/Z 468,466,464 (max 8%)), 338,340 (M+H, 25%), 178(20%), 162 (100%), 132 (20%).

¹ H NMR (CDCl₃, 400 MHz, ppm): δ1.89 (br s, 1H), 3.08 (dd, J=12.5, 2.9,1H), 3.23 (td, J=12.2, 3.6, 1H), 3.59 (dd, J=11.3, 2.5, 1H), 4.03 (td,J=11.7, 3, 1 H), 4.09 (d, J=2.4, 1H), 4.37 (d, J=13.5, 1H), 4.62 (d,J=13.3, 1H), 4.67 (d, J=2.5, 1 H), 6.72 (d, J=1.8, 2H), 7.14 (t, J=1.8,1 H), 7.25-7.40 (m, 5H).

EXAMPLE 452-(S)-(3,5-dichlorobenzyloxy)-4-(3-(5-oxo-1,2,4-triazolo)-methyl)-3-(S)-phenylmorpholineStep A: N-Methylcarboxy-2-chloroacetamidrazone

A solution of 5.0 g (66.2 mmol) of chloroacetonitrile in 35 mL of drymethanol was cooled to 0° C. and was treated with 0.105 g (1.9 mmol) ofsodium methoxide. The ice-bath was removed and the mixture was allowedto stir at room temperature for 30 minutes. To the reaction was thenadded 0.110 mL (1.9 mmol) of acetic acid and then 5.8 g (64.9 mmol) ofmethyl hydrazinecarboxylate. After stirring 30 minutes at roomtemperature, the suspension was concentrated in vacuo, and placed on thehigh-vac line overnight, to give 10.5 g (98%) of a yellow powder, aportion of which was employed in Step C below.

Step B:4-(2-(N-Methylcarboxy-acetamidrazono)-2-(S)-(3,5-dichlorobenzyloxy)-3-(S)-phenylmorpholine

A solution of 0.050 g (0.15 mmol) of 2-(S)-(3,5-dichlorobenzyloxy)-3-(S)-phenylmorpholine (from Example 44, StepC), 0.034 g (0.21 mmol) of N-methyl-carboxy-2-chloroacteamidrazone (fromStep A), and 0.044 mL (0.25 mmol) N,N-diisopropylethylamine in 1 mL ofacetonitrile was stirred at room temperature for 3 hours. The mixturewas partitioned between 20 mL of methylene chloride and 10 mL of water.The layers were separated, the organic layer was dried over sodiumsulfate and was then concentrated in vacuo. The residue was purified byflash chromatography on 35 g of silica eluting with I L of 50: 1:methylene chloride/methanol then 500 mL of 25:1:0.05 methylenechloride:methanol:aqueous ammonia to give 70 mg (˜100%) of the productas a white solid.

Mass Spectrum (FAB): m/Z 469 (M+H, 60%), 467 (M+H, 100%),291 (40%), 160(20%), 158 (25%).

¹ H NMR (CDCl₃, 400 MHz, ppm): δ2.48 (td, J=3.5, 12.2, 1H), 2.53 (d,J=14.6, 1H), 2.90 (d, J=11.8, 1H), 3.37 (d, J=14.6, 1H), 3.52 (d,J=2.8), 1H), 3.62 (dm, J=11.4, 1H), 3.75 (s, 3H), 4.14 (td, J=2.2, 11.8,1H), 4.28 (d, J=13.5, 1H), 4.58 (d, J=13.6), 4.60 (d, J=2.8, 1H), 5.45(br s, 2H), 6.74 (d, J=1.9, 2H), 7.15 (t, J=1.9, 1H), 7.30-7.46 (m, 6H).

Step C: 2-(S)-(3,5-Dichlorobenzyloxy)-4-(3-(5-oxo-1,2,4-triazolo)-methyl)-3-(S)-phenylmorpholine

A solution of 0.069 g (0.15 mmol) of 4-(2-(N-methyl-carboxyacetamidrazono)-2-(S)-(3,5-dichlorobenzyloxy)-3-(S)-phenylmorpholine(from Step B) in 6 mL of xylenes was heated at reflux for 2 hours. Thesolution was cooled and concentrated in vacuo. The residue was purifiedby flash chromatography on 35 g of silica gel eluting with 500 mL of50:1:0.1 methylene chloride/methanol/aqueous ammonia then 500 mL of20:1:0.1 methylene chloride/methanol/aqueous ammonia to give 56 mg (88%)of the product as a white powder.

Mass Spectrum (FAB): m/Z 437 (M+H, 65%), 435 (M+H, 100%), 259 (85%), 161(55%).

¹ H NMR (CDCl₃, 400 MHz, ppm): δ2.53 (t, J=11.7, 3.6, 1H), 2.88(d,J=11.6, 1H), 2.96 (d, J=14.3, 1H), 3.54 (d, J=2.6, 1H), 3.63 (dd,J=11.6, 1.9, 1H), 3.68 (d, J=14.6, 1H), 4.16 (t, J=11.7, 2.2, 1H), 4.30(d, J=13.6), 4.58 (d, J=2.7, 1 H), 4.67 (d, J=13.6, 1H), 6.65 (d, J=1.8,2H), 7.07 (t, J=1.9, 1H), 7.29-7.44 (m, 5H), 10.25 (br s, 1H), 10.75 (brs, 1H).

EXAMPLE 462-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-4-(methoxy-carbonylmethyl)-3-(S)-phenylmorpholine

A solution of 300 mg (0.74 mmole) of2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-morpholine (fromExample 15, Step C) and 0.35 mL (2.0 mmole) of DIEA in 5 mL ofacetonitrile was treated with 0.19 mL (2.0 mmole) of methyl bromoacetateand the mixture was stirred for 16 hr at room temperature. The solutionwas then concentrated in vacuo and the residue partitioned between 30 mLof ether and 15 mL of 0.5 N aqueous KHSO4. The layers were separated andthe organic phase was washed with 10 mL of brine and dried overmagnesium sulfate. Following filtration, the organic phase wasconcentrated in vacuo and the residue purified by flash chromatographyon 20 g of silica eluting with 80:20 hexanes:ether to give 351 nag (99%)of the product. a!_(D) =+147.3° (c=1.6, CHCl₃).

Mass Spectrum (FAB): m/Z 478 (M+H, 40%), 477 (65%), 418 (50%), 250(95%), 234 (90%), 227 (100%).

¹ H NMR (CDCl₃, 400 MHz, ppm): δ3.02 (br d, 2H), 3.13 (d, J=16.9, 1H),3.36 (d, J=16.8), 3.62 (s, 3H), 3.69 (dt, J=11.7, 2.2, 1H), 4.03 (br s,1H), 4.23-4.32 (m, 1H), 4.44 (d, J=13.3, 1H), 4.68, (d, J=2.6, 1H), 4.81(d, J=13.5, 1H), 7.30-7.38 (m, 3H), 7.4-7.5 (m, 3H), 7.70 (s, 1H).

Analysis Calcd for C₂₂ H₂₁ F₆ NO₄ : C, 55.35; H, 4.43; N, 2.93; F, 23.88

Found: C, 55.09; H, 4.43; N, 2.83; F, 24.05

EXAMPLE 472-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-4-(carboxymethyl)-3-(S)-phenylmorpholine

A solution of 0.016 g (0.034 mmole) of2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-4-(methoxy-carbonylmethyl)-3-(S)-phenylmorpholine(from Example 46) in 2 mL of THF and 0.5 mL of water was treated with0.027 mL (0.067 mmole) of 2.5 N aqueous sodium hydroxide and the mixturewas stirred at room temperature for 5 hr. The mixture was treated with 2drops of 2N aqueous HCl and 3 mL of water and the solution was extractedwith 15 mL of 1:1 hexanes:ethyl acetate. The organic phase was driedover magnesium sulfate, filtered and concentrated in vacuo. The residuewas purified by flash chormatography on 13 g of silica eluting with 250mL of 100:3:0.1 methylene chloride:methanol:acetic acid then 100 mL of50:2:0.1 methylene chloride:methanol:acetic acid to give 0.014 g (90%)of an oil.

Mass Spectrum (FAB): m/Z 464 (M+H, 90%), 420 (M-CO2, 10%), 227 (ArCH₂,35%), 220 (M-OCH2Ar, 100%), 161 (20%).

¹ H NMR (CDCl₃, 400 MHz, ppm): δ2.9 (app d, 2H), 3.03 (d, 1H), 3.33 (d,1H), 3.72 (d, 1H), 3.90 (d, 1H), 4.25 (t, 1 H), 4.44 (d, 1H), 4.71 (d,1H), 4.79 (d, 1 H), 7.3-7.4 (m, 5H), 7.44 (s, 2H), 7.71 (s, 1H).

EXAMPLE 482-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-4-((2-aminoethyl)amino-carbonylmethyl)-3-(S)-phenylmorpholine hydrochloride

A solution of 54 mg (0.11 mmole) of 2-(S)-(3,5-bis(tri-fluoromethyl)benzyloxy)-4-(carboxymethyl)-3-(S)-phenylmorpholine (fromExample 46) and 0.15 mL of ethylenediamine (2.3 mmole) in 1 mL ofmethanol was stirred at 55° C. for 48 hr. The mixture was concentratedand the residue purified by flash chromatography on 16 g of silicaeluting with 500 mL of 50:4:0.1 methylene chloride:methanol: aqueousammonia to provide 57 mg(100%) of an oil. The oil was dissolved in etherand was treated with ether saturated with gaseous HCl. Afterconcentration in vacuo, 58 mg (95%) of a rigid oil was obtained.

Mass Spectrum (FAB; free base): m/Z 506 (M+H, 100%), 418 (15%),262(35%), 227 (30%), 173 (40%)

¹ H NMR (CDCl₃, 400 MHz, ppm): δ2.56 (d, J=15.5, 1H), 2.59 (td, J=12.0,3.6, 1H), 2.82 (t, J=6.5, 2H), 2.96 (d, J=11.8, 1H), 3.21 (d, J=15.8,1H), 3.25-3.40 (m, 2H), 3.65 (d, J=2.6, 1H), 3.67 (app dt, J=11.4, ,-2,1H), 4.18 (td, J=11.8, 2.6, 1H), 4.33 (d, J=13.5, 1H),4.69 (d, J=2.7,1H), 4.79 (d, J=13.5, 1H), 7.25-7.40 (m, 5H), 7.46 (s, 2H), 7.59 (br t,1H), 7.71 (s, 1H).

EXAMPLE 492-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-4-((3-amino-propyl)aminocarbonylmethyl)-3-(S)-phenylmorpholine hydrochloride

A solution of 59 mg (0.12 mmole) of 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(carboxymethyl)-3-(S)-phenylmorpholine (from Example 46)and 0.21 mL of 1,3-propylenediamine (2.5 mmole) in 1 mL of methanol wasstirred at 55° C. for 72 hr. The mixture was concentrated and theresidue purified by flash chromatography on 16 g of silica eluting with500 mL of I0:1:0.05 methylene chloride:methanol: aqueous ammonia toprovide 56 mg (88%) of an oil. The oil was dissolved in methylenechloride and was treated with methylene chloride saturated with gaseousHCl. After concentration in vacuo, a white paste was obtained.

Mass Spectrum (FAB; free base): m/Z 520 (M+H, 100%), 418 (10%),276(30%), 227 (20%), 174 (30%)

¹ H NMR (CDCl₃, 400 MHz, ppm): δ1.64 (pentet, J=6.6, 2H), 2.53 (d,J=15.5, 1H), 2.58 (td, J=12.0, 3.6, 1H), 2.73 (t, J=6.5, 2H), 2.92 (d,J=11.8, 1H), 3.19 (d, J=15.8, 1 H), 3.25-3.40 (m, 2H), 3.62 (d, J=2.6,1H), 3.65 (app dt, J=11.4, .˜2, 1H), 4.16 (td, J=11.8, 2.6, 1H), 4.41(d, J=13.5, 1H),4.68 (d, J=2.7, 1H), 4.79 (d, J=13.5, 1H), 7.25-7.40 (m,5H), 7.45 (s, 2H), 7.57 (br t, 1 H), 7.70 (s, 1H).

EXAMPLE 50 4-benzyl-5-(S),6-(R)-dimethyl-3-(S)-phenylmorpholinone and4-benzyl -5-(R),6-(S)-dimethyl-3-(S)-phenylmorpholinone

To a suspension of 1.7 g (7.0 mmole) of N-benzyl-(S)-phenylglycine(Example 13) in 15 ml of methylene chloride at 0° C. was added 6.9 ml(13.9 mmole) of trimethylaluminum (2.0 M in toluene). After one hour at0° C., 0.625 ml (7.0 mmole) of (+/-)-trans-2,3-epoxy butane (dissolvedin 2.0 ml of methylene chloride) was added dropwise and then allowed tostir at 22° C. for 16 hours. The reaction was then transferred toanother flask containing 30 ml of 1:1 hexane:methylene chloride and 30ml of 1M potassium sodium tartrate and stirred at 22° C. for 2 hours.The layers were separated, and the aqueous layer was extracted withmethylene chloride (3×100 ml). The combined organic layers were washedwith 25 ml of a saturated sodium chloride solution, dried over anhydroussodium sulfate, filtered, and concentrated in vacuo.

The crude alcohol was dissolved in 25 ml of toluene, treated with 93 mg(0.49 mmole) of p-toluenesulfonic acid and heated at 50° C. for 20hours. The reaction was then cooled and concentrated in vacuo. Theresidue was partitioned between 15 ml of diethyl ether and 10 ml ofsaturated sodium bicarbonate. The layers were separated, and the organiclayer was washed with water (3×10 ml). The combined organic layers werewashed with 25 ml of a saturated sodium chloride solution, dried overanhydrous magnesium sulfate, filtered, and concentrated in vacuo. Flashchromatography on 145 g of silica gel using 1:4 v/v ethyl acetate/hexaneas the eluant afforded 567 mg of the high R_(f) lactone (Isomer A) and388 mg of the low R_(f) lactone (Isomer B).

¹ H-NMR (400 MHz, CDCl₃) a Isomer A: 1.04 (d, 3H, J=8.0 Hz), 1.24 (d,3H, J=8.0 Hz), 2.92 (br qd, 1 H), 3.41 (d, 1H, J=16.0 Hz), 3.62 (d, 1H,J=16.0 Hz), 4.38 (s, 1 H), 4.96 (br qd, 1H), 7.20-7.42 (m, 8H),7.58-7.64 (m, 2H); Isomer B: 1.04 (d, 3H, J=10.0 Hz), 1.39 (d, 3H,J=10.0 Hz), 3.06 (br qd, 1H), 3.53 (d, 1H, J=16.0 Hz), 3.81 (d, 1H,J=16.0 Hz), 4.33 (s, 1H), 4.67 (br qd, 1H), 7.18-7.50 (m, 10H).

Mass Spectrum (FAB): m/z Isomer A: 296 (M+H, 100%), 294 (50%);

Isomer B: 296 (M+H, 100%), 294 (50%).

EXAMPLE 51 2-(R)-(3,5-Bis(trifluoromethyl)benzyloxy)- 5-(S),6-(R) or5-(R),6-(S)dimethyl!-3-(S)-phenylmorpholinone Step A:4-Benzyl-2-(R)-(3,5-bis(trifluoromethyl)-benzyloxy)- 5-(S),6-(R) or5-(R),6-(S)-dimethyl!-3-(S)-phenyl -morpholinone

According to the procedure in Example 15, Step B, 25 1 mg (0.85 mmole)of Isomer A from Example 50 (4-benzyl- 5-(S),6-(R) or5-(R)-6-(S)-dimethyl!-3-(S)-phenylmorpholinone) provided 238 mg (53%) ofthe product as an oil.

¹ H-NMR (400 MHz, CDCl₃) a 1.03 (d, 3H, J=6.7 Hz), 1.13 (d, 3H, J=6.6Hz), 2.61 (qd, 1H, J=2.2 & 6.6 Hz), 3.26 (d, 1H, J=13.9 Hz), 3.55 (d,1H, J=13.9 Hz), 3.63 (d, 1 H, J=7.6 Hz), 4.01 (qd, 1H, J=2.3 & 6.6 Hz),4.44 (d, 1H, J=13.1 Hz), 4.53 (d, 1H, J=7.7 Hz), 4.71 (s, 1H), 4.85 (d,1 H, J=13.2 Hz), 7.20-7.35 (m, 9H), 7.46-7.48 (m, 2H), 7.67 (s, 1H),7.81 (s, 1H).

Mass Spectrum (FAB): m/z 523 (M+H, 100%), 296 (95%), 280 (40%), 227 (50%).

Step B: 2-(R)-(3,5-Bis(trifluoromethyl)benzyloxy)- 5-(S),6-(R) or 5-(R),6-(S)-dimethyl!-3-(S)-phenylmorpholinone

According to the procedure in Example 15, Step C, 260 mg of startingmaterial from Step A derived from Isomer A in Example 50(4-Benzyl-2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)- 5-(S),6-(R) or5-(R), 6-(S)-dimethyl!-3-(S)-phenylmorpholinone)!provided 122 mg (57%)of the product as an oil.

¹ H-NMR (400 MHz, CDCl₃) δ1.19 (d, 3H, J=6.5 Hz), 1.27 (d, 3H, J=6.7Hz), 2.97 (qd, 1H, J=2.9 & 6.9 Hz), 3.96 (d, 1H, J=7.7 Hz), 4.08-4.11(m, 2H), 4.39 (d, 1H, J=7.7 Hz), 4.50 (d, 1H, J=13.3 Hz), 4.88 (d, 1H,J=13.2 Hz), 7.27-7.33 (m, 3H), 7.40-7.42 (m, 4H), 7.67 (s, 1 H).

Mass Spectrum (FAB): m/z 434 (M+H, 45%), 227 (35%), 206 (40%), 190(100%).

EXAMPLE 52 2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)- 5-(R),6-(S) or5-(S),6-(R) -dimethyl!-3-(S)-phenylmorpholinone Step A:4-Benzyl-2-(S)-(3,5-bis(trifluoromethyl)-benzyloxy)- 5-(R),6-(S) or5-(S),6-(R)-dimethyl!-3-(S)-phenyl -morpholinone

According to the procedure in Example 15, Step B, 449 mg (1.52 mmole) ofIsomer B from Example 50 (4-benzyl- 5-(R),6-(S) or5-(S)-6-(R)-dimethyl!-3-(S)-phenylmorpholinone) provided 400 mg (51%) ofthe product as an oil.

¹ H-NMR (400 MHz, CDCl₃) δ0.90 (d, 3H, J=6.8 Hz), 1.37 (d, 3H, J=6.6Hz), 2.86-2.89 (br qd, 1H), 3.47 (d, 1H, J=15.0 Hz), 3.82-3.85 (m, 2H),3.99-4.02 (br qd, 1H), 4.45 (d, 1H, J=13.6 Hz), 4.81 (d, 1H, J=2.0 Hz),4.87 (d, 1 H, J=13.5 Hz), 7.17-7.83 (m, 13H).

Step B: 2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)- 5-(S),6-(R) or 5-(R),6-(S)-dimethyl-3 -(S)-phenylmorpholinone

According to the procedure in Example 15, Step C, 400 mg of startingmaterial from Step A derived from Isomer B in Example 50(4-Benzyl-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)- 5-(R),6-(S) or5-(S), 6-(R)-dimethyl!-3-(S)-phenylmorpholinone)!provided 230 mg (69%)of the product as an oil.

¹ H-NMR (400 MHz, CDCl₃) δ1.08 (d, 3H, J=6.7 Hz), 1.38 (d, 3H, J=7.0Hz), 3.41-3.45 (br qd, 1H), 3.85-3.89 (br qd, 1H), 4.16 (d, 1H, J=2.9Hz), 4.49 (d, 1H, J=13.6 Hz), 4.71 (d, 1H, J=2.9 Hz), 4.82 (d, 1H,J=13.6 Hz), 7.25-7.36 (m, 7H), 7.66 (s, 1H).

Mass Spectrum (FAB): m/z 434 (M+H, 35%), 227 (40%), 206 (40%), 190(100%).

EXAMPLE 532-(R)-(3,5-Bis(trifluoromethyl)benzyloxy)-4-(3-(1,2,4-triazolo)-methyl)- 5-(S),6-(R) or 5-(R),6-(S)-dimethyl!-3-(S)-phenylmorpholinone

A mixture of 62 mg (0.14 mmole) of 2-(R)-(3,5-Bis(tri-fluoromethyl)benzyloxy)- 5-(S),6-(R) or5-(R),6-(S)-dimethyl!-3-(S)-phenylmorpholinone (from Example 51, StepB), 62 mg (0.45 mmole) of anhydrous potassium carbonate and 26 mg (0.19mmole) of N -formyl-2-chloroacetamidrazone (from Example 17, Step A) in2.0 ml of N,N-dimethylformamide was heated to 60° C. for 2 hours andthen 118° C. for 1.5 hours. The mixture was then allowed to cool to roomtemperature and then quenched with 5 mls of water and diluted with 15mls of ethyl acetate. The layers were separated and the organic layerwas washed with ethyl acetate (2×10 mls). The combined organic layerswere washed with 10 mls of brine, dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo. Flash chromatography on 42g of silica gel using 95:5 v/v methylene chloride/ methanol as theeluant afforded 42 mg (57%) of a clear oil.

¹ H-NMR (400 MHz, CDCl₃) δ1.13 (d, 3H, J=6.5 Hz), 1.19 (d, 3H, J=6.5Hz), 2.65 (qd, 1 H, J=1.9 & 6.5 Hz), 3.58 (d, 1H, J=15.5 Hz), 3.65 (d,1H, J=7.7 Hz), 3.75 (d, 1H, J=15.4 Hz), 4.06 (qd, 1H, J=2.2 & 6.6 Hz),4.45 (d, 1H, J=13.2 Hz), 4.54 (d, 1H, J=7.7 Hz), 4.84 (d, 1H, J=13.2Hz), 7.28-7.37 (m, 7H), 7.67 (s, 1H), 7.89 (s, 1H).

Mass Spectrum (FAB): m/z 516 (M+H, 52%), 287 (28%), 271 (100%), 227(40%), 202 (38%).

EXAMPLE 542-(R)-(3,5-Bis(trifluoromethyl)benzyloxy)-4-(3-(5-oxo-1,2,4-triazolo)methyl)- 5-(S),6-(R) or 5-(R),6-(S)-dimethyl!-3-(S)-phenylmorpholinone

A solution of 96 mg (0.22 mmole) of2-(R)-(3,5-Bis(trifluoromethyl)benzyloxy)- 5-(S),6-(R) or5-(R),6-(S)-dimethyl!-3-(S)-phenylmorpholinone (from Example 51, StepB), 92 mg (0.66 mmole) of potassium carbonate and 48 mg (0.29 mmole) ofN -methylcarboxy-2-chloroacetamidrazone (from Example 18, Step A) in 4mL of DMF was heated at 60° C. for 1.5 hr and at 120° C. for 3.5 hr. Themixture was cooled to room temperature and was partitioned between 15 mLof water and 25 mL of ethyl acetate. The aqueous layer was extractedwith 3×10 mL of ethyl acetate, the combined organic layers were washedwith 10 mL of brine, dried over sodium sulfate, filtered andconcentrated in vacuo. The residue was partly purified by flashchromatography on 42 g of silica gel using 2L of 98:2 v/v methylenechloride/methanol as the eluant and the rich cuts were purified underthe same conditions to give 38 nag (33%) of a clear oil.

¹ H-NMR (400 MHz, CDCl₃) a 1.09 (d, 3H, J=6.5 Hz), 1.20 (d, 3H, J=6.6Hz). 2.64 (qd, 1H, J=2.4 & 6.6 Hz), 3.33 (s, 1H), 3.56 (d, 1H, J=7.6Hz), 4.11 (qd, 1H, J=2.4 & 6.6 Hz), 4.41 (d, 1H, J=13.2 Hz), 4.57 (d, 1H, J=7.7 Hz), 4.82 (d, 1H, J=13.2 Hz), 7.25-7.30 (m, 5H), 7.40 (d, 2H,J=5.7 Hz), 7.65 (s, 1H), 9.46 (s, 1H), 10.51 (s, 1H).

Mass Spectrum (FAB): m/z 531 (M+H, 98%), 287 (100%), 227 (80%), 189(65%).

EXAMPLE 552-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-4-(3-(1,2,4-triazolo)-methyl) -15-(R).6-(S) or 5-(S),6-(R)-dimethyl!-3-(S)-phenylmorpholinone

According to the procedure in Example 53, 75 mg (0.17 mmole) of2-(S)-(3,5-Bis(trifluoromethyl)-benzyloxy)- 5-(R),6-(S) or5-(S),6-(R)-dimethyl!-3-(S)-phenylmorpholinone (from Example 52, Step B)provided, after flash chromatography on 73 g of silica gel using 98:2v/v methylene chloride/methanol as the eluant, 46 mg (52%) of a yellowoil.

¹ H-NMR (400 MHz, CDCl₃) δ1.04 (d, 3H, J=6.6 Hz), 1.46 (d, 3H, J=6.7Hz), 3.05-3.08 (m, 1H), 3.74-3.81 (m, 2H), 3.91-3.95 (m, 2H), 4.41 (d,1H, J=13.2 Hz), 4.69 (d, 1H, J=3.2 Hz), 4.82 (d, 1H, J=13.5 Hz),7.31-7.35 (m, 5H), 7.43-7.45 (m, 2H), 7.68 (s, 1H), 7.91 (s, 1 H).

Mass Spectrum (EI): m/z 432 (36%), 287 (60%), 270 (65%), 227 (30%), 187(48%), 83 (100%).

EXAMPLE 562-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-4-(3-(5-oxo-1,2,4-triazolo)methyl)- 5-(R),6-(S) or 5-(S),6-(R)-dimethyl!-3-(S)-phenylmorpholinone

According to the procedure in Example 54, 86 mg (0.2 mmole) of2-(S)-(3,5-Bis(trifluoromethyl)-benzyloxy)- 5-(R),6-(S) or5-(S),6-(R)-dimethyl!-3-(S)-phenylmorpholinone (from Example 47, Step B)provided, after flash chromatography on 73 g of silica gel using 95:5v/v methylene chloride/methanol as the eluant, 32 mg (30%) of a yellowoil.

¹ H-NMR (400 MHz, CDCl₃) δ1.03 (d, 3H, J=6.7 Hz), 1.40 (d, 3H, J=6.8Hz), 3.00 (qd, 1H, J=3.8 & 6.8 Hz), 3.44 (d, 1H, J=16.1 Hz), 3.63 (d,1H, J=16.0 Hz), 3.82 (d, 1H, J=3.3 Hz), 3.95 (qd, 1H, J=3.7 & 6.7 Hz),4.43 (d, 1H, J=13.5 Hz). 4.73 (d, 1H, J=3.3 Hz), 4.84 (d, 1H, J=13.6Hz), 7.28-7.47 (m, 7H), 7.68 (s, ill), 9.52 (d, 2H).

Mass Spectrum (FAB): m/z 531 (M+H, 100%), 287 (55%), 227 (25%), 147 (50%).

EXAMPLE 57 2-(S)-(3,5-Bis (trifluoromethyl)benzyloxy)-4-(2-(1-(4-benzyl)piperidino) ethyl)-3-(S)-phenylmorpholine

To a solution of 2-(S)-(3,5-bis(trifluoro-methyl)-benzyloxy)-3-(S)-phenylmorpholine (50 mg, 0.12 mmol) and 4-benzyl-1-(2-chloroethyl)piperidine hydrochloride (50 mg, 0.18 mmol) inacetonitrile (0.5 mL) was added diisopropylethylamine (0.065 mL, 0.36mmol) at room temperature. After 60 hours, TLC (5% MeOH/2% Et₃ N/93%EtOAc) indicated that the reaction was only partially complete. Thereaction was diluted with methylene chloride and washed with water, thenbrine, dried over sodium sulfate and evaporated. Prep TLC (5% MeOH/2%Et3N/93% EtOAc) afforded 36 mg (50%) of the title compound as an oil.

¹ H-NMR (400 MHz, CDCl₃) δ1.1-1.4 (m, 2 H), 1.4-1.65 (2 m, 4 H),1.65-2.05 (m, 3 H), 2.05-2.3 (m, 1H), 2.35-2.5 (m and d, J=7 Hz, 3 H),2.55 (br t, J=I 1 Hz, 1 H), 2.65-2.8 (m, 2 H), 3.09 (d, J=11 Hz, 1 H),3.50 (d, J=2.5 Hz, 1 H), 3.66 (dd, J=2 and 11 Hz, 1 H), 4.15 (dt, J =2and 12 Hz, 1 H), 4.38 and 4.75 (AB q, J=13 Hz, 2 H), 4.61 (d, J=2.5 Hz,1 H), 7.06 (d, J=7 Hz, 2 H), 7.15 (t, J=7 Hz, 1 H), 7.2-7.35 (m, 5 H),7.36 (m, 4 H), 7.75 (s, 1H).

EXAMPLE 58 (S)-(4,Fluorophenyl)glycine Via Chiral Synthesis: Step A:3-(4-fluorophenyl)acetyl-4-(S)-benzyl-2-oxazolidinone

An oven-dried, 1 L 3-necked flask, equipped with a septum, nitrogeninlet, thermometer, and a magnetic stirring bar, was flushed withnitrogen and charged with a solution of 5.09 g (33.0 mmol) of4-fluorophenylacetic acid in 100 mL of anhydrous ether. The solution wascooled to -10° C. and treated with 5.60 mL (40.0 mmol) of triethylaminefollowed by 4.30 mL (35.0 mmol) of trimethylacetyl chloride. A whiteprecipitate formed immediately. The resulting mixture was stirred at-10° C. for 40 minutes, then cooled to -78° C.

An oven-dried, 250 mL round bottom flask, equipped with a septum and amagnetic stirring bar, was flushed with nitrogen and charged with asolution of 5.31 g (30.0 mmol) of 4-(S)-benzyl-2-oxazolidinone in 40 mLof dry THF. The solution was stirred in a dry ice/acetone bath for 10minutes, then 18.8 mL of 1.6 M n-butyllithium solution in hexanes wasslowly added. After 10 minutes, the lithiated oxazolidinone solution wasadded, via cannula, to the mixture in the 3-necked flask. The coolingbath was removed from the resulting mixture and the temperature wasallowed to rise to 0° C. The reaction was quenched with 100 mL ofsaturated aqueous ammonium chloride solution, transferred to a 1 Lflask, and the ether and THF were removed in vacuo. The concentratedmixture was partitioned between 300 mL of methylene chloride and 50 mLof water and the layers were separated. The organic layer was washedwith 200 mL of 2 N aqueous hydrochloric acid solution, 300 mL ofsaturated aqueous sodium bicarbonate solution, dried over magnesiumsulfate and concentrated in vacuo. Flash chromatography on 400 g ofsilica gel using 3:2 v/v hexanes/ether as the eluant afforded 8.95 g ofan oil that slowly solidified on standing. Recrystallization from 10:1hexanes/ether afforded 7.89 g (83%) of the title compound as a whitesolid, mp 64°-66° C.

Mass Spectrum (FAB): m/Z 314 (M+H, 100%), 177 (M-ArCH2CO+H, 85%).

¹ H-NMR (400 MHz, CDCl₃): δ2.76 (dd, 1 H, J=13.2, 9.2), 3.26 (dd,J=13.2, 3.2), 4.16-4.34 (m, 4 H), 4.65-4.70 (m, 1 H), 7.02-7.33 (m, 9H).

Analysis: Calcd for C₁₈ H₁₆ FNO₃ : C, 69.00; H, 5.15; N, 4.47; F, 6.06

Found: C, 68.86; H, 5.14; N, 4.48; F, 6.08

Step B:3-((S)-Azido-(4-fluorophenyl))acetyl-4-(S)-benzyl-2-oxazolidinone

An oven-dried, 1 L 3-necked flask, equipped with a septum, nitrogeninlet, thermometer, and a magnetic stirring bar, was flushed withnitrogen and charged with a solution of 58.0 mL of 1 M potassiumbis(trimethylsilyl)amide solution in toluene and 85 mL of THF and wascooled to -78° C. An oven-dried, 250 mL round-bottomed flask, equippedwith a septum and a magnetic stirring bar, was flushed with nitrogen andcharged with a solution of 7.20 g (23.0 mmol) of3-(4-fluorophenyl)acetyl-4-(S)-benzyl-2-oxazolidinone (from Example 58,Step A) in 40 mL, of THF. The acyl oxazolidinone solution was stirred ina dry ice/acetone bath for 10 minutes, then transferred, via cannula, tothe potassium bis(trimethylsilyl)amide solution at such a rate that theinternal temperature of the mixture was maintained below -70° C. Theacyl oxazolidinone flask was rinsed with 15 mL of THF and the rinse wasadded, via cannula, to the reaction mixture and the resulting mixturewas stirred at -78° C. for 30 minutes. An oven-dried, 250 mLround-bottomed flask, equipped with a septum and a magnetic stirringbar, was flushed with nitrogen and charged with a solution of 10.89 g(35.0 mmol) of 2,4,6-triisopropylphenylsulfonyl azide in 40 mL of THF.The azide solution was stirred in a dry ice/acetone bath for 10 minutes,then transferred, via cannula, to the reaction mixture at such a ratethat the internal temperature of the mixture was maintained below -70°C. After 2 minutes, the reaction was quenched with 6.0 mL of glacialacetic acid, the cooling bath was removed and the mixture was stirred atroom temperature for 18 hours. The quenched reaction mixture waspartitioned between 300 mL of ethyl acetate and 300 mL of 50% saturatedaqueous sodium bicarbonate solution. The organic layer was separated,dried over magnesium sulfate, and concentrated in vacuo. Flashchromatography on 500 g of silica gel using 2:1 v/v, then 1:1 v/vhexanes/methylene chloride as the eluant afforded 5.45 g (67%) of thetitle compound as an oil.

IR Spectrum (neat, cm-1): 2104, 1781, 1702.

¹ H-NMR (400 MHz, CDCl₃): δ2.86 (dd, 1 H, J=13.2, 9.6), 3.40 (dd, 1 H,J=13.2, 3.2), 4.09-4.19 (m, 2 H), 4.62-4.68 (m, 1 H), 6.14 (s, 1 H),7.07-7.47 (m, 9 H).

Analysis: Calcd for C₁₈ H₁₅ FN₄ O₃ : C, 61.01; H, 4.27; N, 15.81; F,5.36

Found: C, 60.99; H, 4.19; N, 15.80; F, 5.34

Step C: (S)-Azido-(4-fluorophenyl)acetic acid

A solution of 5.40 g (15.2 mmol) of3-((S)-azido-(4-fluorophenyl))acetyl-4-(S)-benzyl-2-oxazolidinone (fromExample 58, Step B) in 200 mL of 3:1 v/v THF/water was stirred in an icebath for 10 minutes. 1.28 g (30.4 mmol) of lithium hydroxide monohydratewas added in one portion and the resulting mixture was stirred cold for30 minutes. The reaction mixture was partitioned between 100 mL ofmethylene chloride and 100 mL of 25% saturated aqueous sodiumbicarbonate solution and the layers were separated. The aqueous layerwas washed with 2×100 mL of methylene chloride and acidified to pH 2with 2 N aqueous hydrochloric acid solution. The resulting mixture wasextracted with 2×100 mL of ethyl acetate; the extracts were combined,washed with 50 mL of saturated aqueous sodium chloride solution, driedover magnesium sulfate, and concentrated in vacuo to afford 2.30 g(77%;) of the title compound as an oil that was used in the followingstep without further purification.

IR Spectrum (neat, cm-1): 2111, 1724.

¹ H-NMR (400 MHz, CDCl₃): is 5.06 (s, 1 H), 7.08-7.45 (m, 4 H), 8.75 (brs, 1 H).

Step. D: (S)-(4-fluorophenyl)glycine

A mixture of 2.30 g (11.8 mmol) of (S)-azido-(4-fluorophenyl)acetic acid(from Example 58, Step C), 250 mg 10% palladium on carbon catalyst and160 mL 3:1 v/v water/acetic acid was stirred under an atmosphere ofhydrogen for 18 hours. The reaction mixture was filtered through Celiteand the flask and filter cake were rinsed well with ˜1 L of 3:1 v/vwater/acetic acid. The filtrate was concentrated in vacuo to about 50 mLof volume. 300 mL of toluene was added and the mixture concentrated toafford a solid. The solid was suspended in 1:1 v/v methanol/ether,filtered and dried to afford 1.99 g (100%) of the title compound.

¹ H-NMR (400 MHz, D20 +NaOD): δ3.97 (s, 1 H), 6.77 (app t, 2 H, J =8.8),7.01 (app t, 2 H, J=5.6).

Via Resolution: Step A': 4-fluorophenylacetyl chloride

A solution of 150 g (0.974 mol) of 4-fluorophenylacetic acid an 1 mL ofN,N-dimethylformamide in 500 mL of toluene at 40° C. was treated with 20mL of thionyl chloride and heated to 40° C. An additional 61.2 mL ofthionyl chloride was added dropwise over 1.5 hours. After the addition,the solution was heated at 50° C. for 1 hour, the solvent was removed invacuo and the residual oil was distilled at reduced pressure (1.5 mmHg)to afford 150.4 g (89.5%) of the title compound, bp=68°-70° C.

Step B': Methyl 2-bromo-2-(4-fluoro)-phenylacetate

A mixture of 150.4 g (0.872 mol) of 4-fluorophenylacetyl chloride (fromExample 58, Step A') and 174.5 g (1.09 mol) of bromine was irradiated at40°-50° C. with a quartz lamp for 5 hours. The reaction mixture wasadded dropwise to 400 mL of methanol and the solution was stirred for 16hours. The solvent was removed in vacuo and the residual oil wasdistilled at reduced pressure (1.5 mmHg) to afford 198.5 g (92%) of thetitle compound, bp=106°-110° C.

Step C': Methyl (±)-(4-fluorophenyl)glycine

A solution of 24.7 g (0.1 mol) of methyl 2-bromo-2-(4-fluoro)phenylacetate (from Example 58, Step B') and 2.28 g (0.01 mol) of benzyltriethylammonium chloride in 25 mL of methanol was treated with 6.8 g(0.105 mol) of sodium azide and the resulting mixture was stirred 20hours at room temperature. The reaction mixture was filtered; thefiltrate was diluted with 50 mL of methanol and hydrogenated in thepresence of 0.5 g of 10% Pd/C at 50psi for 1 hour. The solution wasfiltered and the solvent removed in vacuo. The residue was partitionedbetween 10% aqueous sodium carbonate solution and ethyl acetate. Theorganic phase was washed with water, saturated aqueous sodium chloridesolution, dried over magnesium sulfate and concentrated in vacuo toafford 9.8 g of the title compound as an oil.

Step D': Methyl (S)-(4-fluorophenyl)glycinate

A solution of 58.4 g of methyl (+)-4-fluorophenylglycinate (from Example58, Step C') in 110 mL of 7:1 v/v ethanol/water was mixed with asolution of 28.6 g (0.0799 mol) of O,O'-(+) -dibenzoyltartaric acid((+)-DBT) (28.6g, 0.0799mol) in 110 mL of 7:1 v/v ethanol: water and theresulting solution was allowed to age at room temperature. Ethyl acetate(220ml) was added after crystallization was complete and the resultingmixture was cooled to -20° C. and filtered to afford 32.4 g of methyl(S)-(4-fluorophenyl) glycinate, (+)-DBT salt (ee=93.2%). The motherliquors were concentrated in vacuo and the free base was liberated bypartitioning between ethyl acetate and aqueous sodium carbonatesolution. A solution of free base, so obtained, in 110 mL of 7:1 v/vethanol/water was mixed with a solution of 28.6 g (0.0799 mol) ofO,O'-(-)-dibenzoyltartaric acid ((-)-DBT) (28.6g, 0.0799mol) in 110 mLof 7:1 v/v ethanol: water and the resulting solution was allowed to ageat room temperature. Ethyl acetate (220ml) was added aftercrystallization was complete and the resulting mixture was cooled to-20° C. and filtered to afford 47.0 g of methyl (R)-(4-fluorophenyl)glycinate, (-)-DBT salt (ee=75.8%). Recycling of the mother liquors andaddition of (+)-DBT gave a second crop of 7.4 g of (S)-(4-fluorophenyl)glycinate, (+)-DBT salt (ee=96.4%). The two crops of the (S)-amino ester(39.8 g) were combined in 200 mL of 7:1 v/v ethanol/water, heated for 30minutes and cooled to room temperature. Addition of ethyl acetate,cooling, and filtration afforded 31.7 g of (S)-(4-fluorophenyI)glycinate, (+)-DBT salt (ee>98%). Enatiomeric excesses was determined bychiral HPLC (Crownpak CR(+) 5% MeOH in aqHClO₄ pH2 1.5ml/min 40° C 200nm).

A mixture of 17.5 g of (S)-(4-fluorophenyl) glycinate, (+)-DBT salt and32 mL of 5.5 N HCl (32ml) was heated at reflux for 1.5 hours. Thereaction mixture was concentrated in vacuo and the residue was dissolvedin 40 mL of water. The aqueous solution was washed 3×30 mL of ethylacetate and the layers were separated. The pH of the aqueous layer wasadjusted to 7 using ammonium hydroxide and the precipitated solid wasfiltered to afford 7.4 g of the title compound (ee =98.8%).

EXAMPLE 59 3-(S)-(4-fluorophenyl)-4-benzyl-2-morpholinone Step A:N-Benzyl (S)-(4-fluorophenyl)glycine

A solution of 1.87 g (11.05 mmol) of (S)-(4-fluorophenyl)glycine (fromExample 58) and 1.12 mL (11.1 mmol) of benzaldehyde in 11.1 mL of 1 Naqueous sodium hydroxide solution and 11 mL of methanol at 0° C. wastreated with 165 mg (4.4 mmol) of sodium borohydride. The cooling bathwas removed and the resulting mixture was stirred at room temperaturefor 30 minutes. Second portions of benzaldehyde (1.12 mL (11.1 mmol))and sodium borohydride 165 mg (4.4 mmol) were added to the reactionmixture and stirring was continued for 1.5 hours. The reaction mixturewas partitioned between 100 mL of ether and 50 mL of water and thelayers were separated. The aqueous layer was separated and filtered toremove a small amount of insoluble material. The filtrate was acidifiedto pH 5 with 2 N aqueous hydrochloric acid solution and the solid thathad precipitated was filtered, rinsed well with water, then ether, anddried to afford 1.95 g of the title compound.

¹ H-NMR (400 MHz, D₂ O+NaOD): δ3.33 (AB q, 2 H, J=8.4), 3.85 (s, 1 H),6.79-7.16 (m, 4 H).

Step B: 3-(S)-(4-fluorophenyl)-4-benzyl-2-morpholinone

A mixture of 1.95 g (7.5 mmol) of N-benzyl (S)-(4-fluorophenyl)glycine,3.90 mL (22.5 mmol) of N,N-diisopropylethylamine, 6.50 mL (75.0 mmol) of1,2-dibromoethane and 40 mL of N,N-dimethylformamide was stirred at 100°C. for 20 hours (dissolution of all solids occurred on warming). Thereaction mixture was cooled and concentrated in vacuo. The residue waspartitioned between 250 mL of ether and 100 mL of 0.5 N potassiumhydrogen sulfate solution and the layers were separated. The organiclayer was washed with 100 mL of saturated aqueous sodium bicarbonatesolution, 3×150 mL of water, dried over magnesium sulfate, andconcentrated in vacuo. Flash chromatography on 125 g of silica gel using3:1 v/v hexanes/ether as the eluant afforded 1.58 g (74%) of the titlecompound as an oil.

¹ H-NMR (400 MHz, CDCl₃): δ2.65 (dt, 1 H, J=3.2, 12.8), 3.00 (dt, 1 H,J=12.8, 2.8), 3.16 (d, 1 H, J=13.6), 3.76 (d, 1 H, J=13.6), 4.24 (s, 1H), 4.37 (dt, 1 H, J=13.2, 3.2), 4.54 (dt, 1 H, J=2.8, 13.2), 7.07 -7.56(m, 9 H).

EXAMPLE 60 2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-(4-fluorophenyl)-4-benzylmorpholine

The title compound was prepared in 72% yield from 3-(S)-(4-fluorophenyl)-4-benzyl-2-morpholinone (from Example 59) usingprocedures analogous to those in Example 15, Steps A and B.

¹ H-NMR (200 MHz, CDCl₃): δ2.37 (dt, 1 H, J=3.6, 11.8), 2.83-2.90 (m, 2H), 3.55-3.63 (m, 2 H), 3.85 (d, 1 H, J=13.4), 4.14 (dt,.1 H, J=2.0,11.8), 4.44 (d, 1 H, J=13.6), 4.66 (d, 1 H, J=2.8), 4.79 (d, 1 H, J=13.4), 7.00-7.70 (12 H).

EXAMPLE 612-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-(4-fluorophenyl)morpholine

The title compound was prepared in 70% yield from 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-(4-fluorophenyl)-4benzylmorpholine(from Example 60) using a procedure analogous to that in Example 15,Step C.

Mass Spectrum (FAB): m/Z 424 (M+H, 40%).

¹ H-NMR (400 MHz, CDCl₃): δ1.80 (br s, 1 H), 3.11 (app dd, 1 H, J=2.2,12.4), 3.25 (dt, 1 H, J=3.6, 12.4), 3.65 (app dd, 1 H, J=3.6, 11.4),4.05 (dt, 1 H, J=2.2, 11.8), 4.11 (d, 1 H, J=2.2), 4.53 (d, 1 H,J=13.6), 4.71 (d, 1 H, J=2.2), 4.83 (d, 1 H, J=13.6), 7.04 (t, 2 H, J=7.2), 7.33-7.37 (m, 2 H), 7.42 (s, 2 H), 7.72 (s, 1 H).

EXAMPLE 622-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H-1,2,4-triazolo))-methylmorpholine

The title compound was prepared in 69% yield from 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-(4-fluorophenyl)morpholine(from Example 61) using a procedure analogous to that in Example 18.

Mass Spectrum (FAB): m/Z 521 (M+H, 100%).

¹ H-NMR (400 MHz, CDCl₃): δ2.55 (dt, 1 H, J=3.6, 12.0), 2.91 (d, 1 H,J=11.6), 2.93 (d, 1 H, J=14.4), 3.57 (d, 1 H, J=2.8), 3.59 (d, 1 H,J=14.4), 3.67-3.70 (m, 1 H), 4.18 (dt, 1 H, J=2.4, 11.6), 4.48 (d, 1 H,J=13.6), 4.65 (d, 1 H, J=2.8), 4.84 (d, 1 H, J=13.6), 7.07 (t, 2 H, J=8.4), 7.40 (s, 2 H), 7.45-7.48 (m, 2 H), 7.68 (s, 1 H), 10.04 (br s, 1H), 10.69 (br s, 1 H).

Analysis: Calcd for C₂₂ H₁₉ F₇ N₄ O₃ : C, 50.78; H, 3.68; N, 10.77; F,25.55

Found: C, 50.89; H, 3.76; N, 10.62; F, 25.56

EXAMPLE 632-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-4-((3-pyridyl)-methylcarbonyl)-3-(R)-phenylmorpholine

A solution of 55 mg (0.315 mmol) of 4-pyridylacetic acid in 1 mL of CH₂Cl₂, containing 0.079 mL (0.715 mmol) of N-methylmorpholine, 53 mg (0.37mmol) of HOBt and 73 mg (0.37 mmol) of EDC was stirred for 10 min. Asolution of 2-(S)-(3,5-bis(tri-fluoromethyl)benzyloxy)-3-(R)-phenylmorpholine (from Example 33) in 1mL of CH₂ Cl₂ was added. After stirring the mixture for 2 h, it waspartitioned between water and CH₂ Cl₂. The organic layer was washed withwater, brine and dried by filtering through Na₂ SO₄. The filtrate wasconcentrated and the residue was purified by flash chromatography using70% EtOAc/hexane to furnish 152 mg (100% yield) of the product.

¹ H-NMR (400 MHz, CDCl₃): δ3.0-3.85 (m, 5H), 3.95 & 4.4 (br s, 1H), 4.66(d, J=13 Hz, 1 H), 4.82 (d, J=13 Hz, 1H), 5.0 & 5.9 (br s, 1 H), 5.23(s, 1H), 7.1-7.65 (m, 7H), 7.8 (m, 3 H), 8.43 (br s, 2H).

EXAMPLE 642-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-4-(methoxycarbonylpentyl)-3-(R)-phenylmorpholine

To a solution of 0.259 g (0.64 mmol) of2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenylmorpholine (fromexample 33) in 2 mL of DMF were added 0.16 g (0.77 mmol) of methyl6-bromohexanoate, 0.155 g (1.12 mmol) of K₂ CO₃ and 2 crystals of nBu₄NI. The resulting solution was heated in a 60° C. bath for 36 h, atwhich time a tic indicated incomplete reaction. The bath temperature wasraised to 100° C. After 3 h the reaction mixture was cooled and dilutedwith EtOAc. The EtOAc solution was washed with water (2×), brine anddried over Na₂ SO₄. The filtrate was concentrated and the residue waschromatographed using 30% EtOAc/hexane to isolate 220 mg (65%) of theproduct.

¹ H-NMR (400 MHz, CDCl₃): δ1.0-1.4 (m, 4 H), 1.47 (m, J=8 Hz, 2H), 1.95(m, 1H), 2.2 (t, J=8 Hz, 2H), 2.35 (m, 2H), 2.9 (d, J=13 Hz, 1H), 3.07(d, J=7 Hz, 1H), 3.62 (s, 3H), 3.81 (td, J=8 Hz and 2 Hz, 1 H), 4.04(dd, J=10 Hz and 2 Hz, 1H), 4.36 (d, J=7 Hz, 1H), 4.4 (d, J=13 Hz, 1H),4.79 (d, J=13 Hz, 1H), 7.2-7.4 (m, 7H), 7.66 (s, 1H).

EXAMPLE 652-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-4-(carboxypentyl)-3-(R)-phenylmorpholine

A solution of 0.15 g (0.28 mmol) of2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-4-(methoxycarbonylpentyl)-3-(R)-phenylmorpholine (from Example 64) in 3 mL of MeOH was saponified bytreating with 0.5 mL of 5 N NaOH for 40 min at 65° C. The solution wascooled, concentrated and the residue was diluted with water. The aqueoussolution was adjusted to pH 6 by adding 2 N HCl and it was extractedwith EtOAc. The organic layer was washed with brine, dried andconcentrated. The residue upon chromatography on a flash column with 50%EtOAc/hexane furnished 0.13g (89%) of the product

¹ H-NMR (400 MHz, CDCl₃): δ1.0-1.5 (m, 4H), 1.5 (m, 2H), 2.2 (m, 2H),2.35 (m, 2H), 2.9 (d, J=13 Hz, 1 H), 3.08 (d, J=7 Hz, 1H), 3.82 (t, J=8Hz, 1 H), 4.09 (d, J=7 Hz, 1H), 4.38 (s, 1H), 4.4 (d, J=13 Hz, 1H), 4.79(d, J=13 Hz, 1 H), 7.2-7.4 (m, 7H), 7.66 (s, 1H).

EXAMPLE 66 2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-4-(methylaminocarbonylpentyl)-6-oxo-hexyl)-3-(R)-phenylmorpholine

A solution of 116 mg (0.22 mmol) of2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-4-(carboxypentyl)3-(R)-phenylmorpholine(from Example 65) in I mL of CH2C12 was treated with 40 mg (0.29 mmol)of HOBt, 57 mg (0.29 mmol) of EDC and 0.037 mL of N-methylmorpholine.After 10 min 0.027 mL (0.3 mmol) of aqueous methylamine (40%) was addedand the resulting mixture was stirred for 4 h. The reaction mixture wasdiluted with water and extracted with CH₂ Cl₂. The combined CH₂ Cl₂layer was washed with water, brine and dried over Na₂ SO₄, and thefiltrate was concentrated. Purification of the residue on a flash columnwith EtOAc furnished 0.10 g of the product.

¹ H-NMR (400 MHz, CDCl₃): δ1.0-1.4 (m, 4 H), 1.47 (m, 2H), 1.95 (m, 1H),2.04 (t, J=8 Hz, 2H), 2.35 (m, 2H), 2.74 (d, J=5 Hz, 3 H), 2.89(d, J=12Hz, 1H) 3.08 (d, J=7 Hz, 1H), 3.81 (t, J=7 Hz, 1H), 4.02 (d, J=11 Hz,1H), 4.36 (d, J=7 Hz, 1H), 4.39 (d, J=13 Hz, 1H), 4.79 (d, J=13 Hz, 1H),5.03 (br s, 1H), 7.2-7.4 (m, 7H), 7.65 (s, 1H).

EXAMPLE 672-(R)-(3,5-Bis(trifluoromethyl)benzoyloxy)-3-(S)-phenyl-4-benzylmorpholine

A solution of 2.67 g (10.0 mmol) of 3-(S)-phenyl-4-benzyl-2-morpholinone (from Example 14) in 40 mL of dry THF was cooled to -78°C. The cold solution was treated with 12.5 mL of 1.0 M L-Selectride®,solution in THF, maintaining the internal reaction temperature below-70° C. The resulting solution was stirred cold for 45 minutes and thereaction was charged with 3.60 mL (20.0 mmol) of3,5-bis(trifluoro-methyl)benzoyl chloride. The resulting yellow mixturewas stirred cold for 30 minutes and the reaction was quenched with 50 mLof saturated aqueous sodium bicarbonate solution. The quenched mixturewas partitioned between 300 mL of ether and 50 mL of water and thelayers were separated. The organic layer was dried over magnesiumsulfate. The aqueous layer was extracted with 300 mL of ether; theextract was dried and combined with the original organic layer. Thecombined organics were concentrated in vacuo. Flash chromatography on150 g of silica gel using 37:3 v/v hexanes/ether as the eluant afforded4.06 g (80%) of the title compound as a solid.

¹ H NMR (CDCl₃, 200 MHz, ppm): a 2.50 (dt, J=3.4, 12.0, 1H), 2.97 (appd, J=12.0, 1H), 2.99 (d, J=13.6, 1 H), 3.72-3.79 (m, 1H), 3.82 (d,J=2.6, 1H), 4.00 (d, J=13.6, 1H), 4.20 (dt, J=2.4, 11.6), 6.22 (d,J=2.6, 1H), 7.22-7.37 (m, 7H), 7.57 (app d, J=6.8, 2H), 8.07 (s, 1H),8.47 (s, 2H).

Analysis Calcd for C₂₆ H₂₁ F₆ NO₃ : C, 61.29; H, 4.16; N, 2.75; F,22.38.

Found: C, 61.18; H, 4.14; N, 2.70; F, 22.13.

EXAMPLE 682-(R)-(1-(3,5-Bis(trifluoromethyl)-phenyl)ethenyloxy)-3-(S)-phenyl-4benzylmorpholine Step A: Dimethyl titanocene

A solution of 2.49 g (10.0 mmol) of titanocene dichloride in 50 mL ofether in the dark at 0° C. was treated with 17.5 mL of 1.4 Mmethyllithium solution in ether maintaining the internal temperaturebelow 5° C. The resulting yellow/orange mixture was stirred at roomtemperature for 30 minutes and the reaction was quenched by slowlyadding 25 g of ice. The quenched reaction mixture was diluted with 50 mLof ether and 25 mL of water and the layers were separated. The organiclayer was dried over magnesium sulfate and concentrated in vacuo toafford 2.03 g (98%) of the title compound as a light-sensitive solid.The dimethyl titanocene could be stored as a solution in toluene at 0°C. for at least 2 weeks without apparent chemical degradation.

¹ H NMR (CDCl₃, 200 MHz, ppm): δ-0.15 (s, 6H), 6.06 (s, 10H).

Step B:2-(R)-(1-(3,5-Bis(trifluoromethyl)-phenyl)ethenyloxy)-3-(S)-phenyl-4-benzylmorpholine

A solution of 2.50 g (4.9 mmol) of 2-(R)-(3,5-bis(tri-fluoro-methyl)benzoyloxy)-3-(S)-phenyl-4-benzyl morpholine (fromExample 67) and 2.50 g (12.0 mmol) of dimethyl titanocene (from Example68. Step A) in 35 mL of 1:1 v/v THF/toluene was stirred in an oil bathat 80° C. for 16 hours. The reaction mixture was cooled and concentratedin vacuo. Flash chromatography on 150 g of silica gel using 3:1 v/vhexanes/methylene chloride as the eluant afforded 1.71 g (69%) of thetitle compound as a solid.

Mass Spectrum (FAB): m/Z 508 (M+H, 25%).

¹ H NMR (CDCl₃, 400 MHz, ppm): δ2.42 (dt, J=3.6, 12.0, 1H), 2.89 (app d,J=11.6), 2.92 (d, J=13.6, 1H), 3.61-3.66 (m, 1H), 3.73 (d, J=2.8), 1H),4.00 (d, J=13.6, 1H), 4.09 (dt, J=2.4, 11.6, 1H), 4.75 (d, J=2.8, 1H),4.79 (d, J=2.8, 1 H), 5.36 (d, J=2.4, 1H), 7.23-7.41 (m, 7H), 7.63 (appd, J=7.2, 2H), 7.79 (s, 1 H), 7.91 (s, 2H).

Analysis Calcd for C₂₇ H₂₃ F₆ NO₂ : C, 63.90; H, 4.57; N, 2.76; F,22.46.

Found: C, 63.71; H, 4.53; N, 2.68; F, 22.66.

EXAMPLE 692-(R)-(1-(S)-(3,5-Bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-phenylmorpholine and 2-(S)-(l-(R)-(3,5-Bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-phenylmorpholine

A mixture of 1.50 g (2.9 mmol) of 2-(R)-(1-(3,5-bis(tri-fluoromethyl)-phenyl)ethenyloxy)-3-(S)-phenyl-4-benzyl morpholine (fromExample 68) and 750 mg 10% palladium on carbon catatlyst in 25 mL of 3:2v/v isopropanol/ethyl acetate was stirred under an atmosphere ofhydrogen for 48 hours. The catalyst was filtered onto a pad of Celite;the reaction flask and filter pad were rinsed with 500 mL of ethylacetate. The filtrate was concentrated in vacuo. Flash chromatography on60 g of silica gel using 2:1 v/v hexanes/ether, then 2:1 v/vhexanes/ether afforded 106 mg of 2-(R)-(1-(S)-(3,5-bis(tri-fluoromethyl)-phenyl)ethoxy)-3-(S)-phenyl morpholine and 899 mg of2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-phenylmorpholine, both as oils (84% total yield).

For 2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-phenylmorpholine:

Mass Spectrum (Cl): m/Z 420 (M⁺, 20%), 178 (100%).

¹ H NMR (CDCl₃, 400 MHz, ppm): δ1.46 (d, J=6.8), 1.92 (br s, 1H), 3.13(dd, J=3.0, 12.6, 1 H), 3.24 (dt, J=3.6, 12.6, 1H), 3.62 (dd, J=3.6,11.2), 4.04 (d, J=2.4, 1H), 4.14 (dt, J=3.0, 11.2, 1H), 4.48 (d, J=2.4,1H), 4.90 (q, J=6.8, 1H), 7.21-7.32 (m, 7H), 7.64 (s, 1H).

Analysis Calcd for C₂₀ H₁₉ F₆ NO₂ : C, 57.28; H, 4.57; N, 3.34; F,27.18.

Found: C, 57.41; H, 4.61; N, 3.29; F, 27.23.

EXAMPLE 702-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methylmorpholineStep A:2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-phenyl-4-(2-(N-methylcarboxy-acetamidrazono)morpholine

A solution of 945 mg (2.3 mmol) of2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-phenylmorpholine (from Example 69), 447 mg (2.7 mmol) ofN-methylcarboxy-2-chloroacetamidrazone (from Example 45, Step A), and0.78 mL (4.5 mmol) of N,N-diisopropylethylamine in 17 mL of acetonitrilewas stirred at room temperature for 20 hours. The reaction wasconcentrated in vacuo and the residue was partitioned between 50 mL ofmethylene chloride and 25 mL of water. The organic layer was separated,dried over magnesium sulfate and concentrated in vacuo. Flashchromatography on 50 g of silica gel using 50:1:0.1 methylenechloride/methanol/ammonium hydroxide as the eluant afforded 1.12 g (90%)of the title compound as a foam.

Step B:2-(R)-(l-(R)-(3,5-Bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-phenyl-4.(3,(5-oxo-1,2,4-triazolo)-methylmorpholine

A solution of 1.01 g (1.8 mmol) of2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-phenyl-4-(2-(N-methylcarboxyacetamidrazono)morpholine(from Example 70, Step A) in 15 mL of xylenes was heated at reflux for 2hours. The reaction was cooled and concentrated in vacuo. Flashchromatography on 50 g of silica gel using 50:1:0.1 methylenechloride/methanol/ammonium hydroxide as the eluant afforded 781 mg (76%)of the title compound as a solid.

Mass Spectrum (FAB) m/Z 517 (M+H, 18%), 178 (100%).

¹ H NMR (CDCl₃, 400 MHz, ppm): δ1.47 (d, J=6.8), 2.01-2.05 (m, 2H), 2.55(dt, J=3.6, 12.0, 1 H), 2.91 (d, J=10.8, 1H), 2.95 (d, J=14.8, 1 H),3.49 (d, J=2.4, 1H), 3.65 (d, J=14.8, 1H), 3.69 (d, J=10.8, 1H), 4.29(dt, J=2.4, 10.0), 4.38 (d, J=2.8, 1 H), 4.88 (q, J=6.8, 1H), 7.14 (s,2H), 7.33-7.40 (m, 5H), 7.62 (s, 1H), 9.91 (br s, 1H), 10.16 (br s, 1H).

Analysis Calcd for C₂₃ H₂₂ F₆ N₄ O₃ : C, 53.49; H, 4.06; N, 10.85; F,22.07.

Found: C, 53.64; H, 4.33; N, 10.81; F, 22.27.

EXAMPLE 712-(R)-(1-(S)-(3,5-Bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methylmorpholine

The title compound was prepared in 32% yield from 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-phenyl morpholine(from Example 69) using a procedure analogous to Example 70.

Mass Spectrum (FAB): m/Z 517 (M+H, 100%), 259 (50%).

¹ H NMR (CDCl₃, 400 MHz, ppm): δ1.09 (d, J=6.4, 3H), 2.47-2.53 (m, 1H),2.83 (app d, J=11.6, 1H), 2.95 (d, J=14.0, 1H), 3.51-3.65 (m, 3H), 4.01(app t, J=11.6, 1H), 4.60 (q, J=6.4, 1H), 4.84 (d, J=2.4, 1 H),7.33-7.51 (m, 5H), 7.74 (s, 2H), 7.76 (s, 1H), 9.51 (br s, 1H), 10.00(br s, 1H).

EXAMPLE 722-(R)-(3,5-Bis(trifluoromethyl)benzoyloxy)-3-(S)-(4-fluoro)phenyl-4benzylmorpholine

The title compound was prepared in 83% yield from 3-(R)-(4-fluoro)-phenyl-4-benzyl-2-morpholinone (from Example 59) using aprocedure analogous to Example 67.

Mass Spectrum (FAB): m/Z 528 (M+H, 25%), 270 (100%).

¹ H NMR (CDCl₃, 400 MHz, ppm): δ2.50 (dt, J=3.2, 12.0, 1H), 2.96 (app d,J=12.0, 1H), 2.98 (d, J=13.6, 1H), 3.74-3.78 (m, 1H), 3.81 (d, J=2.8,1H), 3.94 (d, J=13.6, 1H), 4.19 (dt, J=2.0, 12.0), 6.20 (d, J=2.8, 1H),6.99 (t, J=8.4, 2H), 7.27-7.38 (m, 5H), 7.52-7.56 (m, 2H), 8.09 (s, 1H),8.46 (s, 2H).

EXAMPLE 732-(R)-(1-(3,5-Bis(trifluoromethyl)-phenyl)ethenyloxy)-3-(S)-(4-fluoro)-phenyl-4-benzyl morpholine

The title compound was prepared in 60% yield from 2-(R)-(3,5-bis(trifluoromethyl)benzoyloxy)-3-(S)-(4-fluoro)-phenyl-4-benzylmorpholine (Example 72) using a procedure analogous to Example 68.

Mass Spectrum (FAB): m/Z 526 (M+H, 75%), 270 (100%).

¹ H NMR (CDCl₃, 400 MHz, ppm): δ2.42 (dt, J=3.6, 12.0), 2.90 (app d,J=12.0, 1H), 2.91 (d, J=13.6, 1H), 3.62-3.66 (m, 1H), 3.72 (d, J=2.6),3.94 (d, J=13.6, 1H), 4.09 (dt, J=2.4, 12.0, 1 H), 4.75 (d, J=3.2, 1H),4.82 (d, J=3.2, 1H), 5.32 (d, J=2.6, 1H), 7.09 (t, J=8.8, 2H), 7.24-7.33(m, 5H), 7.58-7.62 (m, 2H), 7.80 (s, 1H), 7.90 (s, 2H).

EXAMPLE 742-(R)-(1-(S)-(3,5-Bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenylmorpholine and 2-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)-phenyl)ethoxy)-3z(S)-(4-fluoro)-phenylmorpholine

A mixture of 1.83 g (3.5 mmol) of 2-(R)-(1-(3,5-bis(trifluoromethyl)phenyl)ethenyloxy)-3-(S)-(4-fluoro)-phenyl-4-benzyl morpholine (fromExample 73) and 800 mg 5% rhodium on alumina catalyst in 40 mL ofabsolute ethanol was stirred under an atmosphere of hydrogen for 24hours. The catalyst was filtered onto a pad of Celite; the reactionflask and filter cake were rinsed with 200 mL of ethyl acetate. Thefiltrate was concentrated in vacuo and the residue was pumped under highvacuum (1 mmHg, room temperature) to dryness.

The residue was redissolved in 40 mL of isopropanol; 800 mg of 10%palladium on carbon catalyst was added and the resulting mixture wasstirred under an atmosphere of hydrogen for 24 hours. The catalyst wasfiltered onto a pad of Celite; the reaction flask and filter cake wererinsed with 200 mL of ethyl acetate. The filtrate was concentrated invacuo. Flash chromatography on 50 g of silica gel using 2:1 v/vhexanes/ether, then 3:2 v/v ether/hexanes as the eluant afforded 283 mgof 2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)-phenyl)-ethoxy)-3-(S)-(4-fluoro)-phenyl morpholine and 763 mg of2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenylmorpholine, both as oils (total yield 68%).

For2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenylmorpholine:

Mass Spectrum (FAB) m/Z 438 (M+H, 65%), 180 (100%).

¹ H NMR (CDCl₃, 400 MHz, ppm): δ1.47 (d, J=6.8, 3H), 1.87 (br s, 1H),3.03 (dd, J=2.8, 12.8), 3.17 (dt, J=4.0, 12.4, 1H), 3.43-3.47 (m, 1 H),3.80 (dt, J=3.2, 11.6), 4.10 (d, J=2.2, 1H), 4.70 (q, J=6.8, 1H), 4.87(d, J=2.2, 1H), 6.99-7.03 (m, 2H), 7.23-7.27 (m, 2H), 7.63 (s, 2H), 7.66(s, 1H).

For2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenylmorpholine:

Mass Spectrum (FAB) m/Z 438 (M+H, 75%), 180 (100%).

¹ H NMR (CDCl₃, 400 MHz, ppm): δ1.16 (d, J=6.8), 1.80 (br s, 1H), 3.13(dd, J=3.2, 12.4), 3.23 (dt, J=3.6, 12.4), 3.63 (dd, J=2.4, 11.2), 4.01(d, J=2.4, 1H), 4.13 (dt, J=3.2, 12.0), 4.42 (d, J=2.4, 1H), 4.19 (q,J=6.8, 1H), 7.04-7.09 (m, 2H), 7.27-7.40 (m, 4H), 7.73 (s, 1H).

EXAMPLE 752-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4:(3.-(5-oxo-1,2,4-triazolo)-methylmorpholine

The title compound was prepared in 79% yield from 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)phenylmorpholine (from Example 74) using a procedure anaolgous to Example 70.

Mass Spectrum (FAB): m/Z 535 (M+H, 100%), 277 (60%).

¹ H NMR (CDCl₃ +CD₃ OD, 400 MHz, ppm): δ1.48 (d, J=6.8, 3H), 2.52 (appt, J=10.4, 1H), 2.85-2.88 (m, 2H), 3.47 (d, J=2.8, 1H), 3.63 (d, J=14.4,1H), 3.70 (dd, J=2.0, 11.6, 1H), 4.24 (app t, J=10.8, 1H), 4.35 (d,J=2.8, 1H), 4.91 (q, J=6.8, 1H), 7.07 (app t, J=8.4, 2H), 7.15 (s, 2H),7.37-7.40 (m, 2H), 7.65 (s, 1H).

Analysis Calcd for C₂₃ H₂₁ F₇ N₄ O₃ : C, 51.69; H, 3.96; N, 10.48; F,24.88.

Found: C, 51.74; H, 4.04; N, 10.50; F, 24.59.

EXAMPLE 762-(R)-(1-(S)-(3,5-Bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methylmorpholine

The title compound was prepared in 60% yield from2-(R)((1-(S)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenylmorpholine (from Example 74) using a procedure anaolgous to Example 70.

Mass Spectrum (FAB): m/Z 535 (M+H, 50%), 293 (100%).

¹ H NMR (CDCl₃ +CD₃ OD, 400 MHz. ppm): δ1.11 (d, J=6.4, 3H), 2.49 (dt,J=2.4, 11.2), 2.83 (app d. J=11.2, 1H), 2.95 (d, J=14.4, 1H), 2.48-2.58(m, 3H), 3.99 (app t, J=9.6, 1H), 4.61 (q, J=6.4, 1H), 4.81 (d, J=2.4, 1H), 7.09 (t, J=8.8, 2H), 7.50-7.53 (m, 2H), 7.75 (app s, 3H), 10.40 (brs, 1H), 11.00 (br s, 1H).

EXAMPLE 772-(R)-(1-(R)-(3-(Trifluoromethyl)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2.4-triazolo)-methylmorpholineStep A: 2-(R)-(1-(R)-(3-(Trifluoromethyl)-phenyl)ethoxy)-3-(S) -phenylmorpholine

The title compound was prepared in 25% yield from3-(S)-phenyl-4-benzyl-2-morpholinone (from Example 14) using proceduresanaolgous to Examples 67-69.

¹ H NMR (CDCl₃, 400 MHz, ppm): δ1.39 (d, J=6.6, 3H), 1.93 (br s, 1H),3.10 (dd, J=3.0, 12.7, 1H), 3.20 (dt, J=3.6, 12.4, 1 H), 3.58 (ddd,J=1.1, 3.8, 11.2, 1H), 4.00 (d, J=2.4, 1H), 4.12 (dt, J=3.0, 11.2, 1H),4.44 (d, J=2.4, 1H), 4.79 (q, J=6.6, 1 H), 6.72 (d, J=7.7, 1H), 7.01 (s,1H), 7.09 (t, J=7.7, 1H), 7.18-7.25 (m, 2H), 7.25-7.3 (m, 3H), 7.34 (d,J=7.7, 1H).

Analysis: Calcd for C₁₉ H₁₉ F₃ N₁ O₂ : C-65.14 H-5.47 N-4.00 F-16.27

Found: C-64.89 H-5.73 N-3.83 F-15.95

Step B: 2-(R)-(1-(R)-(3-(Trifluoromethyl)-phenyl)ethoxy)-3-(S)-phenyl-4-(3 -(5 -oxo-1,2,4.-triazolo)-methylmorpholine

The title compound was prepared in 90% yield from2-(R)-(1-(R)-(3-(trifluoromethyl)-phenyl)ethoxy)-3-(S)-phenyl morpholine(from Example 77, Step A) using a procedure anaolgous to Example 70.

¹ H NMR (CDCl₃, 400 MHz, ppm): δ1.40 (d, J=6.3, 3H), 2.53 (br t, J=11.2,1H), 2.86 (app d, J=12.2, 1H), 2.94 (d, J=14.3, 1H), 3.44 (br s, 1H),3.63 (br d, J=14, 2H), 4.27 (app t, J=11.5, 1H), 4.34 (d, J=2.1, 1 H),4.76 (q, J=6.7, 1H), 6.63 (d, J=7.7, 1H), 6.93 (s, 1H), 7.06 (t, J=7.6,1H), 7.25-7.45 (m, 6H), 9.63 (br s, 1H), 9.74 (br s, 1H).

Analysis: Calcd for C₂₂ H₂₂ F₃ N₄ O₃ : C-59.06 H-4.96 N-12.52 F-12.74

Found: C-58.84 H-5.17 N-12.37 F-12.50

EXAMPLE 78 2-(R)-(1-(R)-(3-(Fluoro)-5-(trifluoromethyl)-phenyl)ethoxy)-3-(S) -phenyl-4-(3 -(5 -oxo-1,2,4-triazolo)-methylmorpholine Step A:2-(R)-(1-(R)-(3-(Fluoro)-5-(trifluoromethyl)-phenyl)-ethoxy)-3-(S)-phenyl-morpholine

The title compound was prepared in 44% yield from3-(S)-phenyl-4-benzyl-2-morpholinone (from Example 14) using proceduresanaolgous to Examples 67-69.

¹ H NMR (CDCl₃, 400 MHz, ppm): δ1.38 (d, J=6.6, 3H), 1.90 (br s, 1H),3.17 (dd, J=3.0, 12.7, 1H), 3.18 (dt, J=3.6, 12.7, 1H), 3.58 (ddd,J=1.1, 3.8, 11.2, 1H), 4.02 (d, J=2.3, 1 H), 4.11 (dt, J=3.0, 11.2, 1H), 4.44 (d, J=2.3, 1H), 4.78 (q, J=6.6, 1H), 6.29 (d, J=9.2, 1H), 6.85(s, 1H), 7.03 (d, J=8.4, 1H), 7.18-7.26 (m, 2H), 7.26-7.3 (m, 3H).

Analysis: Calcd for C₁₉ H₁₈ F₄ N₁ O₂ : C-61.95 H-4.93 N-3.80 F-20.63

Found: C-61.78 H-5.14 N-3.71 F-20.35

Step B: 2-(R)-(1-(R)-(3-(Fluoro)-5-(trifluoromethyl)-phenyl)-ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl -morpholine

The title compound was prepared in 77% yield from2-(R)-(1-(R)-(3-(fluoro)-5-(trifluoromethyl)-phenyl)ethoxy)-3-(S)-phenylmorpholine (from Example 78, Step A) using a procedure anaolgous toExample 70.

¹ H NMR (CDCl₃, 400 MHz, ppm): δ1.40 (d, J=6.3, 3H), 2.54 (br t, J=l 1,1H), 2.87 (app d, J=12, 1H), 2.94 (app d, J=14, 1H), 3.47 (br s, 1H),3.63 (br t, J=14, 2H), 4.25 (app t, J=11, 1H), 4.35 (d, J=1.5, 1 H),4.75 (q, J=6.3, 1H), 6.62 (d, J=6.7, 1 H), 6.78 (s, 1 H), 7.01 (d J=8.4,1H), 7.24 (d, J=3.9, 1 H), 7.35 Cot s, 4H), 9.61 (br s, 1H), 9.89 (br s,1H).

Analysis: Calcd for C₂₂ H₂₁ F₄ N₄ O₃ :C-56.77 H-4.55 N-12.04 F-16.33

Found: C-56.57 H-4.65 N-11.94 F-16.13

EXAMPLE 792-(S)-(3-fluoro-5-trifluoromethyl)benzoyloxy)-3-(S)-(4-fluoro)-phenyl-4-benzyl morpholine

The title compound was prepared in 57% yield from 3-(S)-(4-fluoro)-phenyl-4-benzyl-2-morpholinone (from Example 59) using aprocedure analogous to Example 67.

Mass Spectrum (Cl): m/Z 478 (M+H, 100%)

¹ H NMR (CDCl₃, 360 MHz, ppm): δ2.50 (dt, J=3.3, 12.0, 1H), 2.96(d,J=12.0, 1H), 2.98 (d, J=13.6, 1 H), 3.75 (dd,J=1.7, 11.5, 1H), 3.80 (d,J=13.6, 1H), 3.75 (dd, J=1.7, 11.5, 1 H), 3.80 (d, J=2.5, 1H), 3.92 (d,J=13.6, 1H), 4.19 (dt, J=2.1, 12.0, 1H), 6.20 (d,J=2.5, 1H), 6.99 (t,J=8.7, 2H), 7.2-7.37 (m, 5H), 7.51-7.55 (m, 3H), 7.89 (d, J=8.4, 1H),8.09 (s, 1 H).

EXAMPLE 802-(S)-(1-(3-fluoro-5-trifluoromethyl)-phenyl)ethenyloxy)-3-(S)-(4-fluoro)-phenyl-4-benzylmorpholine

The title compound was prepared in 85% yield from2-(S)-(3-fluoro-5-trifluoromethyl)benzoyloxy)-3-(S)-(4-fluoro)-phenyl-4-benzylmorpholine (from Example 79) using a procedure analogous to Example 68.

Mass Spectrum (Cl): m/Z 476 (M+H, 100%)

¹ H NMR (CDCl₃, 360 MHz, ppm): δ2.42 (dt, J=3.6, 12.0 Hz, 1H), 2.90 (d,J=12.0, 1H), 2.91 (d, J=13.6, 1H), 3.60-3.62 (m, 1H), 3.72 (d, J=2.6,1H), 3.92 (d, J=13.6, 1 H), 4.09 (dt, J=2.4, 12.0, 1H), 4.67 (d, J=2.9,1H) 4.76 (d, J=2.9, 1 H), 5.28 (d, J=2.6, 1H), 7.07 (t, J=8.7, 2H),7.2-7.37 (m, 7H), 7.53 (s, 1H), 7.57-7.61 (m, 2H).

EXAMPLE 812-(S)-(1-(S)-(3-fluoro-5-trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenylmorpholine and2-(S)-(1-(R)-(3-fluoro-5-trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenylmorpholine

The title compounds were prepared from2-(S)-(1-(3-fluoro-5-trifluoromethyl)-phenyl)ethenyloxy)-3-(S)-(4-fluoro)-phenyl -4-benzyl morpholine (from Example80) using a procedure analogus to Example 74, but using 10% palladium oncharcoal as the catalyst.

For2-(S)-(1-(S)-(3-fluoro-5-trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenylmorpholine:

Mass Spectrum (Cl): m/Z 388 (M+H, 100%)

¹ H NMR (CDCl₃, 360 MHz, ppm): δ1.12 (d, J=6.5, 1H),1.83 (s, 1H), 3.02(d, J=10.1, 1H), 3.16 (dt, J=3.6,12.5, 1 H), 3.43 (dd, J=2.7, 11.4, 1H),3.81 (dt, J=2.9, 11.7, 1H), 4.09 (d, J=2.1, 1H), 4.62 (q, J=6.5, 1H),4.84 (d, J=2.1, 1H), 7.05 (t, J=8.8, 2H), 7.2 (d, J=8.8, 2H), 7.32 (s,1H), 7.38 (dd, J=5.5, 8.5, 2H).

For2-(S)-(1-(R)-(3-fluoro-5-trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenylmorpholine:

Mass Spectrum (Cl): m/Z 387 (M+, 100%)

¹ H NMR (CDCl₃, 360 MHz, ppm): δ1.42 (d, J=6.6, 3H), 1.91 (s, 1H), 3.11(dd, J=3.2, 12.4, 1 H), 3.22 (dt, J=3.6, 12.4, 1H), 3.58-3.62 (m, 1H),4.01 (d, J=2.3, 1H), 4.11 (dt, J=3.2, 12.0, 1H), 4.41 (d, J=2.3, 1H),4.80 (q, J=6.6, 1H), 6.41 (d, J=9.2, 1 H), 6.86 (s, 1H), 7.02 (t, J=8.7,2H), 7.08 (d, J=9.2, 2H), 7.21-7.26 (m, 2H).

EXAMPLE 822-(S)-(1-(R)-(3-fluoro-5-trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methylmorpholine

The title compound was prepared from2-(S)-(1-(R)-(3-fluoro-5-trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl morpholine (from Example 81)using a procedure analogous to Example 70, mp 209°-211° C.

α!_(D) =+65.1 (c =1.0, methanol)

¹ H NMR (CDCl₃, 360 MHz, ppm): δ1.32 (d, J=6.4, 1H), 2.38 (t, J=11.9,1H), 2.76 (d, J=13.9, 1H), 2.84 (d, J=11.5, 1H), 3.32 (s, 1H),3.40(d,J=13.9, 1H),3.49(s, 1H),3.61 (d,J=11.2, 1H),4.11 (t, J=l 1.3,1H), 4.8 (q, J=6.4, 1H), 6.57 (d, J=9.4, 1H), 6.94 (s, 1H), 7.1 (t,J=8.7, 2H), 7.39 (d, J=8.7, 2It), 7.51 (s, 2H), 11.26 (s, 1H), 11.38 (s,1H).

EXAMPLE 832-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(4-(2-oxo-1,3-imidazolo)-methylmorpholineStep A: N,N-Diacetyl-4-bromomethyl-2-imidazolone

The title compound was prepared according to the procedure of Dolan andDushinsky (Journal of the American Chemical Society, 70, 657 (1948)).

Step B:2-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(4-(2-oxo-1,3-imidazolo)-methyl -morpholine

A mixture of 1.00 g (2.28 mmol) of2-(S)-(1-(R)-(3,5-bis(trifluoro-methyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenylmorpholine (from Example 74), 0.62 g (2.40 mmol) ofN,N-diacetyl-4-bromomethyl-2-imidazolone (from Example 83, Step A) and0.63 g (4.56 mmol) of potassium carbonate in 10 mL ofN,N-dimethylformamide was stirred at room temperature for 15 minutes.The reaction was diluted with 100 mL of ethyl acetate and washed withwater, saturated aqueous sodium chloride solution, dried over magnesiumsulfate, and evaporated in vacuo. The resulting oil was dissolved in 10mL of ethanol; the resulting solution was treated with 1.05 mL of 33%ethanolic methylamine solution and stirred at room temperature for 10minutes. The reaction mixture was concentrated in vacuo to afford asolid. Recrystallisation from ethyl acetate/methanol afforded 0.63 g ofthe title compound, mp 192°-194° C.

¹ H NMR (d6-DMSO, 360 MHz, ppm): δ1.35 (d, J=6.5, 3H), 2.25 (dt, J=8.7,1H), 2.60 (d, J=13.8, 1H), 2.89 (d, J=11.6, 1H), 3.28-3.36 (m, 2H), 3.62(d, J=10.2, 1H), 4.1 (t, J=10.0, 1H), 4.31 (d, J=2.7, 1H), 4.92 (q,J=6.5, 1H), 5.97 (s, 1 H), 7.06 (t, J=8.8, 2H), 7.36 (s, 2H), 7.65-7.85(m, 2H), 7.84 (s, 1 H), 9.58 (s, 1 H), 9.8 (s, 1H).

EXAMPLE 842-(S)-(1-(R)-(3-fluoro-5-(trifluoromethyl)-phenyl)ethoxy-3-(S)-(4-fluoro)-phenyl-4-(4-(2-oxo-1,3-imidazolo)-methylmorpholine

The title compound was prepared from2-(S)-(1-(R)-(3-fluoro-5-trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl morpholine (from Example 82)using a procedure analogous to Example 83, mp 209°-210° C.

α!_(D) =+92.8 (c =1.0, methanol).

¹ H NMR (d6-DMSO, 360 MHz, ppm) δ1.31 (d, J=6.5, 3H), 2.24 (dt, J=3.0,11.9, 1 H), 2.6 (d, J=13.9, 1H), 3.61 (d, J=11.2, 1H), 4.1 (t, J=11.0,1H), 4.29 (d, J=2.3, 1H), 4.8 (q, J=6.5, 1H), 6.00 (s, 1H), 6.55 (d,J=9.3, 1H), 6.94 (s, 1H), 7.11 (t, J=8.7, 2H), 7.39 (d, J=8.4, 1H), 7.51(s, 2H), 9.59 (s, 1H), 9.84 (s, 1 H).

EXAMPLE 852-(S)-(l-(S)-(3,5-Bis(trifluoromethyl)-phenyl)ethoxy)-3-(R)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)-methylmorpholine

The title compound was prepared from (R)-(4-fluoro)-phenylglycine usingprocedures analogous to Example 59, 67, 68, 69 and 70.

α!_(D) =-67.7 (c =0.7, MeOH, 20° C.)

EXAMPLE 86

The following compounds are prepared from3-(S)-phenyl-4-benzyl-2-morpholinone (from Example 14) or3-(S)-(4-fluoro)-phenyl -4-benzyl-2-morpholinone (from Example 59) usingprocedures analogous to Examples 15, 67-69 and 74. The hydrogenation ofthe 1-(substituted-aryl)ethenyloxy intermediates may be done with 10%palladium on carbon (Example 70) or 5% rhodium on alumina catalyst(Example 74) to give rapid reduction of the enol ether. Removal of the4-benzyl substituent may be done catalytically under extendedhydrogenation with 10% palladium on carbon or 5% rhodium on aluminacatalyst or (when dehalogenation or cleavage of the ether might occur)in a second step with 1-chloroethyl chloroformate as in Example 44, StepC.

1)2-(R)-(1-(R)-(3-(chloro)-5-(trifluoromethyl)-phenyl)ethoxy)-3-(S)-phenyl-morpholine;

2) 2-(R)-(1-(R)-(3,5-(dimethyl)-phenyl)ethoxy)-3-(S)-phenylmorpholine;

3)2-(R)-(1-(R)-(3-(fluoro)-5-(methyl)-phenyl)ethoxy)-3-(S)-phenylmorpholine;

4)2-(R)-(1-(R)-(3-(chloro)-5-{methyl)-phenyl)ethoxy)-3-(S)-phenylmorpholine;

5) 2-(R)-(1-(R)-(3 -(bromo)-5-(methyl)-phenyl)ethoxy)-3-(S)-phenylmorpholine;

6) 2-(R)-(1-(R)-(3-(isopropoxy)-phenyl)ethoxy)-3-(S)-phenylmorpholine;

7) 2-(R)-(1-(R)-(3-(isopropoxy)-5-(trifluoromethyl)-phenyl)ethoxy)-3-(S)-phenyl-morpholine;

8) 2-(R)-(1-(R)-(3-(chloro)-5-(isopropoxy)-phenyl)ethoxy)-3-(S)-phenyl-morpholine;

9) 2-(R)-(1-(R)-(3 -(fluoro)-5-(isopropoxy)-phenyl)ethoxy)-3 -(S)-phenyl-morpholine;

10) 2-(R)-(1-(R)-(3-(t-butyl)-phenyl)ethoxy)-3-(S)-phenylmorpholine;

11)2-(R)-(1-(R)-(3-(t-butyl)-5-(chloro)-phenyl)ethoxy)-3-(S)-phenylmorpholine;

12) 2-(R)-(1-(R)-(3 -(t-butyl)-5 -(trifluoromethyl)-phenyl)ethoxy)-3-(S)-phenyl-morpholine;

13) 2-(R)-(1-(R)-(3,5-(dimethyl)-4-(fluoro)-phenyl)ethoxy)-3-(S)-phenyl-morpholine

14) 2-(R)-(1-(R)-(3,5-(dimethyl)-4-(chloro)-phenyl)ethoxy)-3-(S)-phenyl-morpholine;

15) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-4-(fluoro)-phenyl)ethoxy)-3-(S)-phenyl-morpholine;

16) 2-(R)-(1-(R)-(3,5-bis (trifluoromethyl)-4-(chloro)-phenyl)ethoxy)-3-(S)-phenyl-morpholine;

17) 2-(R)-(1-(R)-(3,5-(dichloro)-phenyl)ethoxy)-3-(S)-phenylmorpholine;

18) 2-(R)-(1-(R)-(3,5-(difluoro)-phenyl)ethoxy)-3-(S)-phenylmorpholine;

19) 2-(R)-(1-(R)-(l-(naphthyl)ethoxy)-3-(S)-phenyl-morpholine;

20) 2-(R)-(I-(R)-(1-(4-(fluoro)naphthyl))ethoxy)-3-(S)-phenylmorpholine;

21) 2-(R)-(1-(R)-(l-(3-(fluoro)naphthyl))ethoxy)-3-(S)-phenylmorpholine;

22) 2-(R)-(1-(R)-(1-(3-(chloro)naphthyl))ethoxy)-3-(S)-phenylmorpholine:

23) 2-(R)-(1-(R)-(1-(3-(methyl)naphthyl))ethoxy)-3-(S)-phenylmorpholine;

24) 2-(R)-(1-(R)-(1-(3-(trifluoromethyl)naphthyl))ethoxy)-3-(S)-phenyl-morpholine;

25) 2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy-3-(S)-phenylmorpholine;

26) 2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)phenyl-morpholine;

27) 2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl)-phenylethoxy)-3-(S)-phenyl-morpholine:

28)2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl)-phenylethoxy)-3-(S)-(4-fluoro)phenyl-morpholine;

29) 2-(S)-(2-chloro-5-trifluoromethyl)benzyloxy-3-(S)-phenylmorpholine;

30) 2-(S)-(2-chloro-5-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)phenyl-morpholine;

31) 2-(R)-(1-(R)-(2-chloro-5-trifluoromethyl)-phenylethoxy)-3-(S)-phenyl-morpholine;

32) 2-(R)-(1-(R)-(2-chloro-5-trifluoromethyl)-phenylethoxy)-3-(S)-(4-fluoro)-phenyl-morpholine;

33) 2-(S)-(3-methyl)benzyloxy-3-(S)-phenyl-morpholine;

34) 2-(S)-(3-methyl)benzyloxy-3-(S)-(4-fluoro)-phenyl-morpholine;

35) 2-(R)-(1-(R)-(3-methyl)-phenylethoxy)-3-(S)-phenyl-morpholine;

36)2-(R)-(1-(R)-(3-methyl)-phenylethoxy)-3-(S)-(4-fluoro)-phenylmorpholine;

37) 2-(S)-(3-bromo)benzyloxy-3-(S)-phenyl-morpholine;

38) 2-(S)-(3-bromo)benzyloxy-3-(S)-(4-fluoro)-phenyl-morpholine;

39) 2-(R)-(1-(R)-(3-bromo)-phenylethoxy)-3-(S)-phenyl-morpholine;

40)2-(R)-(1-(R)-(3-bromo)-phenylethoxy)-3-(S)-(4-fluoro)-phenylmorpholine;

41) 2-(S)-(3-chloro)benzyloxy-3-(S)-phenyl-morpholine;

42) 2-(S)-(3-chloro)benzyloxy-3-(S)-(4-fluoro)-phenyl-morpholine;

43) 2-(R)-(1-(R)-(3-chloro)-phenylethoxy)-3-(S)-phenyl-morpholine;

44)2-(R)-(1-(R)-(3-chloro)-phenylethoxy)-3-(S)-(4-fluoro)-phenylmorpholine;

45) 2-(S)-(3-trifluoromethyl)benzyloxy-3-(S)-phenyl-morpholine;

46)2-(S)-(3-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)-phenylmorpholine;

47) 2-(S)-(3-t-butyl)benzyloxy-3-(S)-phenyl-morpholine;

48) 2-(S)-(3-t-butyl)benzyloxy-3-(S)-(4-fluoro)-phenyl-morpholine;

49) 2-(R)-(1-(R)-(3-(thiomethyl)-phenyl)ethoxy)-3-(S)-phenylmorpholine;

50) 2-(R)-(1-(R)-(3-(thiomethyl)-5-(trifluoromethyl)-phenyl)ethoxy)-3-(S)-phenyl-morpholine;

51)2-(R)-(1-(R)-(2,2-(dimethyl)-5-(thiomethyl)-2,3-dihydrobenzofuran-7-yl)ethoxy)-3-(S)-phenyl-morpholine;

52) 2-(R)-(1-(R)-(3,5-(dimethoxy)-phenyl)ethoxy)-3-(S)-phenylmorpholine;

53)2-(R)-(1-(R)-(3-(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-morpholine;

54)2-(R)-(1-(R)-(3-(fluoro)-5-(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-morpholine;

55)2-(R)-(1-(R)-(3-(chloro)-5-(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-morpholine;

56)2-(R)-(1-(R)-(3,5-(dimethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-morpholine;

57)2-(R)-(1-(R)-(3-(fluoro)-5-(methyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-morpholine;

58) 2-(R)-(1-(R)-(3-(chloro)-5-(methyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-morpholine;

59) 2-(R)-(1-(R)-(3-(bromo)-5-(methyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-morpholine;

60)2-(R)-(1-(R)-(3-(isopropoxy)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-morpholine;

61) 2-(R)-(1-(R)-(3-(isopropoxy)-5-(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-morpholine;

61)2-(R)-(1-(R)-(3-(chloro)-5-(isopropoxy)-phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-morpholine:

63)2-(R)-(1-(R)-(3-(fluoro)-5-(isopropoxy)-phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-morpholine:

64)2-(R)-(1-(R)-(3-(t-butyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenylmorpholine;

65) 2-(R)-(1-(R)-(3-(t-butyl)-5-(chloro)-phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-morpholine;

66)2-(R)-(1-(R)-(3-(t-butyl)-5-(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-morpholine;

67)2-(R)-(1-(R)-(3,5-(dimethyl)-4-(fluoro)-phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-morpholine;

68)2-(R)-(1-(R)-(3,5-(dimethyl)-4-(chloro)-phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-morpholine:

69) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-4-(fluoro)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-morpholine;

70) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-4-(chloro)-phenyl)ethoxy) -3-(S)-(4-fluoro)-phenyl-morpholine:

71) 2-(R)-(1-(R)-(3,5-(dichloro)-phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-morpholine;

72) 2-(R)-(1-(R)-(3,5 -(difluoro)-phenyl)ethoxy)-3 -(S)-(4-fluoro)phenyl-morpholine;

73) 2-(R)-(1-(R)-(1-(naphthyl)ethoxy)-3-(S)-(4-fluoro)-phenylmorpholine;

74) 2-(R)-(1-(R)-(1-(4-(fluoro)naphthyl))ethoxy)-3-(S)-(4-fluoro)-phenyl-morpholine;

75) 2-(R)-(1-(R)-(1-(3 -(fluoro)naphthyl) )ethoxy)-3-(S)-(4-fluoro)-phenyl-morpholine;

76) 2-(R)-(I-(R)-(1-(3-(chloro)naphthyl))ethoxy)-3-(S)-(4-fluoro)phenyl-morpholine;

77) 2-(R)-(I-(R)-(1-(3-(methyl)naphthyl))ethoxy)-3-(S)-(4-fluoro)phenyl-morpholine;

78)2-(R)-(1-(R)-(1-(3-(trifluoromethyl)naphthyl))ethoxy)-3-(S)-(4-fluoro)phenyl-morpholine;

79)2-(R)-(1-(R)-(3-(thiomethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-morpholine;

80) 2-(R)-(1-(R)-(3-(thiomethyl)-5-(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-morpholine;

81) 2-(R)-(1-(R)-(2,2-(dimethyl)-5-(thiomethyl)-2,3-dihydro-benzofuran-7-yl)ethoxy)-3-(S)-(4-fluoro)-phenyl-morpholine;

82)2-(R)-(1-(R)-(3,5-(dimethoxy)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-morpholine;

83) 2-(R)-(l-(R)-(phenyl)ethoxy)-3-(S)-phenyl-morpholine;

84) 2-(R)-(1-(R)-(phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-morpholine;

85) 2-(R)-(1-(R)-(3-(fluoro)-phenyl)ethoxy)-3-(S)-phenyl-morpholine;

86)2-(R)-(1-(R)-(3-(fluoro)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenylmorpholine;

87) 2-(R)-(1-(R)-(4-(fluoro)-phenyl)ethoxy)-3-(S)-phenyl-morpholine;

88)2-(R)-(l-(R)-(4-(fluoro)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenylmorpholine;

89)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(3-fluoro-phenyl-morpholine;

90)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(3,4difluoro)phenyl-morpholine;

91)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(3,4dichlorophenyl-morpholine;

92) 2-(R)-(1-(R)-(3,5-b is(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(3,4-dimethyl)-phenyl-morpholine;

93) 2-(R)-(1-(R)-(3,5 -bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-3,4methylenedioxyphenyl-morpholine;

94)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(2-naphthyl-morpholine.

EXAMPLE 87

The following compounds are prepared from the corresponding2-(S)-(substituted-benzyloxy)-3-(S)-aryl morpholines or 2-(R)-(1-(R)-(substituted-aryl)ethoxy)-3-(S)-aryl morpholines (from Example 86)using procedures analogous to Examples 17, 18, 36, 38, 83 or, in thecase of the 4-(5-tetrazolyl)-methyl-substituted morpholines, byalkylation of the morpholine (from Example 86) with chloroacetonitrilein the presence of a tertiary amine base in acetonitrile, followed byformation of the final product by reacting the resulting nitrile witheither sodium azide or trimethylsilylazide in an appropriate solvent.

1)2-(R)-(1-(R)-(3-(Chloro)-5-(trifluoromethylphenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

2)2-(R)-(1-(R)-(3,5-(Dimethyl)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

3) 2-(R)-(1-(R)-(3-(Fluoro)-5-(methyl)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

4) 2-(R)-(1-(R)-(3-(Chloro)-5-(methyl)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

5) 2-(R)-(1-(R)-(3-(Bromo)-5-(methyl)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

6)2-(R)-(1-(R)-(3-(Isopropoxy)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

7) 2-(R)-(1-(R)-(3-(Isopropoxy)-5-(trifluoromethyl)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

8) 2-(R)-(1-(R)-(3-(Chloro)-5-(isopropoxy)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

9) 2-(R)-(1-(R)-(3-(Fluoro)-5-(isopropoxy)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

10) 2-(R)-(1-(R)-(1-(3 -(trifluoromethyl)naphthyl))ethoxy)-3 -(S)-phenyl-4-(3-(-1,2,4-triazolo)-methyl-morpholine;

11) 2-(R)-(1-(R)-(3-(t-Butyl)-5-(chloro)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

12)2-(R)-(1-(R)-(3-(t-Butyl)-5-(trifluoromethyl)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

13) 2-(R)-(1-(R)-(3,5-(Dimethyl)-4-(fluoro)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

14) 2-(R)-(1-(R)-(3,5-(Dimethyl)-4-(chloro)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

15) 2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)-4-(fluoro)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

16) 2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)-4-(chloro)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

17)2-(R)-(1-(R)-(3,5-(Dichloro)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

18)2-(R)-(1-(R)-(3,5-(Difluoro)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

19) 2-(R)-(1-(R)-(1-(Naphthyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

20) 2-(R)-(1-(R)-(1 -(4-(Fluoro)naphthyl))ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

21)2-(R)-(1-(R)-(1-(3-(Fluoro)naphthyl))ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

22)2-(R)-(I-(R)-(1-(3-(Chloro)naphthyl))ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

23)2-(R)-(1-(R)-(1-(3-(Methyl)naphthyl))ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

24) 2-(R)-(1-(R)-(1-(3-(Trifluoromethyl)naphthyl))ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

25)2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

26)2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

27) 2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl)-phenylethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

28) 2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl)-phenylethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

29)2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(3(5-oxo-1,2,4-triazolo)-methyl-morpholine;

30)2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

31) 2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl)-phenylethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

32) 2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl)-phenylethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

33)2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(4-(2-oxo-1,3-imidazolo)-methyl-morpholine;

34) 2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro))-phenyl-4-(4-(2-oxo-1,3-imidazolo)-methyl-morpholine;

35) 2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl)-phenylethoxy)-3-(S)-phenyl-4-(4-(2-oxo-1,3-imidazolo)-methyl-morpholine;

36) 2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl)-phenylethoxy)-3-(S)-(4-fluoro)-phenyl-4-(4-(2-oxo-1,3-imidazolo)-methyl-morpholine;

37)2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(2-imidazolo)-methyl-morpholine;

38) 2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro))-phenyl-4-(2-imidazolo)-methyl-morpholine;

39) 2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl)-phenylethoxy)-3-(S)-phenyl-4-(2-imidazolo)-methyl-morpholine;

40) 2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl)-phenylethoxy)-3-(S)-(4-fluoro)-phenyl-4-(2-imidazolo)-methyl-morpholine;

41) 2-(S)-(2-fluoro-5 -trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(4imidazolo)-methyl-morpholine;

42) 2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro))-phenyl-4-(4-imidazolo)-methyl-morpholine;

43) 2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl)-phenylethoxy)-3-(S)-phenyl-4-(4-imidazolo)-methyl-morpholine;

44) 2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl)-phenylethoxy)-3-(S)-(4-fluoro)-phenyl-4-(4-imidazolo)-methyl-morpholine;

45)2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(5tetrazolo)-methyl-morpholine;

46) 2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro))-phenyl-4-(5-tetrazolo)-methyl-morpholine;

47) 2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl)-phenylethoxy)-3-(S)-phenyl-4-(5-tetrazolo)-methyl-morpholine;

48) 2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl)-phenylethoxy)-3-(S)-(4-fluoro)-phenyl-4-(5-tetrazolo)-methyl-morpholine;

49) 2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(2-oxo-5H-pyrrol-4-yl)-methyl-morpholine;

50)2-(S)-(2-fluoro-5-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)-phenyl-4-(2-oxo-5H-pyrrol-4-yl)-methyl-morpholine;

51) 2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl)-phenylethoxy)-3-(S)-phenyl-4-(2-oxo-5H-pyrrol-4-yl)-methyl-morpholine;

52) 2-(R)-(1-(R)-(2-fluoro-5-trifluoromethyl)-phenylethoxy)-3-(S)-(4-fluoro)-phenyl-4-(2-oxo-5H-pyrrol-4-yl)-methyl-morpholine;

53) 2-(S)-(2-Chloro-5-trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

54)2-(S)-(2-Chloro-5-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

55) 2-(R)-(1-(R)-(2-Chloro-5-trifluoromethyl)-phenylethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

56) 2-(R)-(1-(R)-(2-Chloro-5-trifluoromethyl)-phenylethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

57) 2-(S)-(2-Chloro-5-trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

58)2-(S)-(2-Chloro-5-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

59) 2-(R)-(1-(R)-(2-Chloro-5-trifluoromethyl)-phenylethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

60) 2-(R)-(1-(R)-(2-Chloro-5-trifluoromethyl)-phenylethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

61) 2-(S)-(2-Chloro-5 -trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(4-(2-oxo-1,3 -imidazolo)-methyl-morpholine;

62)2-(S)-(2-Chloro-5-trifluoromethyl)benzyloxy-3-(S)-(4fluoro)-phenyl-4-(4-(2-oxo-1,3-imidazolo)-methyl-morpholine;

63) 2-(R)-(1-(R)-(2-Chloro-5-trifluoromethyl)-phenylethoxy)-3-(S)-phenyl-4-(4-(2-oxo-1,3-imidazolo)-methyl-morpholine;

64) 2-(R)-(1-(R)-(2-Chloro-5-trifluoromethyl)-phenylethoxy)-3-(S)-(4-fluoro)-phenyl-4-(4-(2-oxo-1,3 -imidazolo)-methyl-morpholine;

65) 2-(S)-(2-Chloro-5 -trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(2imidazolo)-methyl-morpholine;

66)2-(S)-(2-Chloro-5-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)-phenyl-4-(2-imidazolo)-methyl-morpholine;

67) 2-(R)-(1-(R)-(2-Chloro-5-trifluoromethyl)-phenylethoxy)-3-(S)-phenyl-4-(2-imidazolo)-methyl-morpholine;

68) 2-(R)-(1-(R)-(2-Chloro-5-trifluoromethyl)-phenylethoxy)-3-(S)-(4-fluoro)-phenyl-4-(2-imidazolo)-methyl-morpholine;

69)2-(S)-(2-Chloro-5-trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(4imidazolo)-methyl-morpholine;

70) 2-(S)-(2-Chloro-5-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro))-phenyl-4-(4-imidazolo)-methyl-morpholine;

71) 2-(R)-(1-(R)-(2-Chloro-5-trifluoromethyl)-phenylethoxy )-3-(S)-phenyl-4-(4-imidazolo)-methyl-morpholine;

72) 2-(R)-(1-(R)-(2-Chloro-5-trifluoromethyl)-phenylethoxy)-3-(S)-(4-fluoro)-phenyl-4-(4-imidazolo)-methyl-morpholine;

73)2-(S)-(2-Chloro-5-trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(5-tetrazolo)-methyl-morpholine;

74) 2-(S)-(2-Chloro-5-trifluoromethyl)benzyloxy-3 -(S)-(4-fluoro))-phenyl-4-(5-tetrazolo)-methyl-morpholine;

75) 2-(R)-(1-(R)-(2-Chloro-5-trifluoromethyl)-phenylethoxy)-3 -(S)-phenyl-4-(5 -tetrazolo)-methyl-morpholine;

76) 2-(R)-(1-(R)-(2-Chloro-5-trifluoromethyl)-phenylethoxy)-3-(S)-(4-fluoro)-phenyl-4-(5-tetrazolo)-methyl-morpholine;

77)2-(S)-(2-Chloro-5-trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(2-oxo-5H-pyrrol-4-yl)-methyl-morpholine;

78)2-(S)-(2-Chloro-5-trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)-phenyl-4-(2-oxo-5H-pyrrol-4-yl)-methyl-morpholine;

79) 2-(R)-(1-(R)-(2-Chloro-5-trifluoromethyl)-phenylethoxy)-3-(S)-phenyl-4-(2-oxo-5H-pyrrol-4-yl)-methyl-morpholine;

80) 2-(R)-(1-(R)-(2-Chloro-5-trifluoromethyl)-phenylethoxy)-3-(S)-(4-fluoro)-phenyl-4-(2-oxo-5H-pyrrol-4-yl)-methyl-morpholine;

81) 2-(S)-(3-Methyl)benzyloxy-3-(S)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

82)2-(S)-(3-Methyl)benzyloxy-3-(S)-(4-fluoro)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

83) s3)2-(R)-(1-(R)-(3-Methyl)-phenylethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

84)2-(R)-(1-(R)-(3-Methyl)-phenylethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

85)2-(S)-(3-Methyl)benzyloxy-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

86) 2-(S)-(3-Methyl)benzyloxy-3-(S)-(4-fluoro)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

87) 2-(R)-(1-(R)-(3-Methyl)-phenylethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

88)2-(R)-(1-(R)-(3-Methyl)-phenylethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

89)2-(S)-(3-Methyl)benzyloxy-3-(S)-phenyl-4-(4-(2-oxo-1,3-imidazolo)-methyl-morpholine;

90) 2-(S)-(3-Methyl)benzyloxy-3-(S)-(4-fluoro)-phenyl-4-(4-(2-oxo-1,3-imidazolo)-methyl-morpholine;

91) 2-(R)-(1-(R)-(3-Methyl)-phenylethoxy)-3-(S)-phenyl-4-(4-(2-oxo-1,3-imidazolo)-methyl-morpholine;

92)2-(R)-(1-(R)-(3-Methyl)-phenylethoxy)-3-(S)-(4-fluoro)-phenyl-4-(4-(2-oxo-1,3-imidazolo)-methyl-morpholine;

93)2-(S)-(3-Methyl)benzyloxy-3-(S)-phenyl-4-(2-imidazolo)-methylmorpholine;

94) 2-(S)-(3-Methyl)benzyloxy-3-(S)-(4-fluoro)-phenyl-4-(2imidazolo)-methyl-morpholine;

95) 2-(R)-(1-(R)-(3 -M ethyl)-phenylethoxy)-3 -(S)-phenyl-4-(2imidazolo)-methyl-morpholine:

96) 2-(R)-(1-(R)-(3 -Methyl)-phenylethoxy)-3-(S)-(4-fluoro)-phenyl-4-(2-imidazolo)-methyl-morpholine;

97)2-(S)-(3-Methyl)benzyloxy-3-(S)-phenyl-4-(4-imidazolo)-methylmorpholine;

98)2-(S)-(3-Methyl)benzyloxy-3-(S)-(4-fluoro)-phenyl-4-(4-imidazolo)-methyl-morpholine;

99)2-(R)-(1-(R)-(3-Methyl)-phenylethoxy)-3-(S)-phenyl-4-(4-imidazolo)-methyl-morpholine;

100)2-(R)-(1-(R)-(3-Methyl)-phenylethoxy)-3-(S)-(4-fluoro)-phenyl-4-(4-imidazolo)-methyl-morpholine;

101) 2-(S)-(3-Methyl)benzyloxy-3-(S)-phenyl-4-(5-tetrazolo)-methylmorpholine;

102) 2-(S)-(3-Methyl)benzyloxy-3-(S)-(4-fluoro)-phenyl-4-(5tetrazolo)methyl-morpholine;

1034) 2-(R)-(1-(R)-(3-Methyl)-phenylethoxy)-3-(S)-phenyl-4-(5tetrazolo)methyl-morpholine;

104) 2-(R)-(1-(R)-(3 -Me thy I )-phenylethoxy)-3-(S)-(4-fluoro)-phenyl-4-(5-tetrazolo)-methyl-morpholine;

105) 2-(S)-(3-Methyl)benzyloxy-3-(S)-phenyl-4-(2-oxo-5H-pyrrol-4yl)-methyl-morpholine;

106) 2-(S)-(3 -Methyl)benzyloxy-3 -(S)-(4-fluoro)-phenyl-4-(2-oxo-pyrrol-4-yl)-methyl-morpholine;

107) 2-(R)-(1-(R)-(3-Methyl)-phenylethoxy)-3-(S)-phenyl-4-(2-oxo-5H-pyrrol-4-yl)-methyl-morpholine;

108)2-(R)-(1-(R)-(3-Methyl)-phenylethoxy)-3-(S)-(4-fluoro)-phenyl-4(2-oxo-5H-pyrrol-4-yl)-methyl-morpholine;

109)2-(S)-(3-Bromo)benzyloxy-3-(S)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

110)2-(S)-(3-Bromo)benzyloxy-3-(S)-(4-fluoro)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine:

111)2-(R)-(1-(R)-(3-Bromo)-phenylethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

112)2-(R)-(1-(R)-(3-Bromo)-phenylethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

113) 2-(S)-(3-Bromo)benzyloxy-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

114) 2-(S)-(3 -Bromo)benzyloxy-3-(S)-(4-fluoro)-phenyl-4-(3 -(5-oxo-1,2,4-triazolo)-methyl-morpholine;

115) 2-(R)-(1-(R)-(3-Bromo)-phenylethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

116)2-(R)-(1-(R)-(3-Bromo)-phenylethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

117) 2-(S)-(3-Bromo)benzyloxy-3-(S)-phenyl-4-(4-(2-oxo-1,3imidazolo)-methyl-morpholine;

118) 2-(S)-(3-Bromo)benzyloxy-3-(S)-(4-fluoro)-phenyl-4-(4-(2-oxo-1,3-imidazolo)-methyl-morpholine;

119) 2-(R)-(1-(R)-(3-Bromo)-phenylethoxy)-3-(S)-phenyl-4-(4-(2-oxo -1,3-imidazolo)-methyl-morpholine;

120)2-(R)-(1-(R)-(3-Bromo)-phenylethoxy)-3-(S)-(4-fluoro)-phenyl-4-(4-(2-oxo-1,3-imidazolo)-methyl-morpholine;

121)2-(S)-(3-Bromo)benzyloxy-3-(S)-phenyl-4-(2-imidazolo)-methylmorpholine;

122)2-(S)-(3-Bromo)benzyloxy-3-(S)-(4-fluoro)-phenyl-4-(2imidazolo)-methyl-morpholine;

123) 2-(R)-(1-(R)-(3-Bromo)-phenylethoxy)-3-(S)-phenyl-4-(2imidazolo)-methyl-morpholine;

124)2-(R)-(1-(R)-(3-Bromo)-phenylethoxy)-3-(S)-(4-fluoro)-phenyl-4-(2-imidazolo)-methyl-morpholine;

125)2-(S)-(3-Bromo)benzyloxy-3-(S)-phenyl-4-(4-imidazolo)-methylmorpholine;

126)2-(S)-(3-Bromo)benzyloxy-3-(S)-(4-fluoro)-phenyl-4-(4imidazolo)-methyl-morpholine;

127)2-(R)-(1-(R)-(3-Bromo)-phenylethoxy)-3-(S)-phenyl-4-(4imidazolo)-methyl-morpholine;

128)2-(R)-(1-(R)-(3-Bromo)-phenylethoxy)-3-(S)-(4-fluoro)-phenyl-4-(4-imidazolo)-methyl-morpholine;

129)2-(S)-(3-Bromo)benzyloxy-3-(S)-phenyl-4-(5-tetrazolo)-methylmorpholine:

130) 2-(S)-(3-Bromo)benzyloxy-3-(S)-(4-fluoro)-phenyl-4-(5tetrazolo)-methyl-morpholine;

131) 2-(R)-(1-(R)-(3-Bromo)-phenylethoxy)-3-(S)-phenyl-4-(5tetrazolo)-methyl-morpholine;

132)2-(R)-(1-(R)-(3-Bromo)-phenylethoxy)-3-(S)-(4-fluoro)-phenyl-4-(5-tetrazolo)-methyl-morpholine;

133) 2-(S)-(3-Bromo)benzyloxy-3 -(S)-phenyl-4-(2-oxo-5H-pyrrol-4-yl)-methyl-morpholine;

134) 2-(S)-(3-Bromo)benzyloxy-3-(S)-(4-fluoro)-phenyl-4-(2-oxo-5H-pyrrol-4-yl)-methyl-morpholine;

135) 2-(R)-(1-(R)-(3-Bromo)-phenylethoxy)-3-(S)-phenyl-4-(2-oxo-5H-pyrrol-4-yl)-methyl-morpholine;

136)2-(R)-(1-(R)-(3-Bromo)-phenylethoxy)-3-(S)-(4-fluoro)-phenyl-4(2-oxo-5H-pyrrol-4-yl)-methyl-morpholine;

137)2-(S)-(3-Chloro)benzyloxy-3-(S)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

138)2-(S)-(3-Chloro)benzyloxy-3-(S)-(4-fluoro)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

139)2-(R)-(1-(R)-(3-Chloro)-phenylethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine:

140)2-(R)-(1-(R)-(3-Chloro)-phenylethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

141)2-(S)-(3-Chloro)benzyloxy-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

142) 2-(S)-(3 -Chloro)benzyloxy-3-(S)-(4-fluoro)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

143) 2-(R)-(1-(R)-(3-Chloro)-phenylethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

144)2-(R)-(1-(R)-(3-Chloro)-phenylethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

145)2-(S)-(3-Chloro)benzyloxy-3-(S)-phenyl-4-(4-(2-oxo-1,3imidazolo)-methyl-morpholine;

146) 2-(S)-(3-Chloro)benzyloxy-3-(S)-(4-fluoro)-phenyl-4-(4-(2-oxo-1,3-imidazolo)-methyl-morpholine;

147) 2-(R)-(1-(R)-(3-Chloro)-phenylethoxy)-3-(S)-phenyl-4-(4-(2-oxo-1,3-imidazolo)-methyl-morpholine;

148) 2-(R)-(1-(R)-(3-Chloro)-phenylethoxy)-3-(S)-(4-fluoro)-phenyl-4-(4-(2-oxo-1,3-imidazolo)-methyl-morpholine;

149)2-(S)-(3-Chloro)benzyloxy-3-(S)-phenyl-4-(2-imidazolo)-methylmorpholine:

150) 2-(S)-(3-Chloro)benzyloxy-3-(S)-(4-fluoro)-phenyl-4-(2imidazolo)methyl-morpholine;

151) 2-(R)-(1-(R)-(3-Chloro)-phenylethoxy)-3-(S)-phenyl-4-(2imidazolo)methyl-morpholine;

152)2-(R)-(1-(R)-(3-Chloro)-phenylethoxy)-3-(S)-(4-fluoro)-phenyl-4-(2-imidazolo)-methyl-morpholine;

153)2-(S)-(3-Chloro)benzyloxy-3-(S)-phenyl-4-(4-imidazolo)-methylmorpholine;

154)2-(S)-(3-Chloro)benzyloxy-3-(S)-(4-fluoro)-phenyl-4-(4-imidazolo)-methyl-morpholine;

155) 2-(R)-(1-(R)-(3-Chloro)-phenylethoxy)-3-(S)-phenyl-4-(4imidazolo)-methyl-morpholine;

156)2-(R)-(1-(R)-(3-Chloro)-phenylethoxy)-3-(S)-(4-fluoro)-phenyl-4-(4-imidazolo)-methyl-morpholine;

157)2-(S)-(3-Chloro)benzyloxy-3-(S)-phenyl-4-(5-tetrazolo)-methylmorpholine;

158) 2-(S)-(3-Chloro)benzyloxy-3-(S)-(4-fluoro)-phenyl-4-(5tetrazolo)-methyl-morpholine;

159) 2-(R)-(1-(R)-(3-Chloro)-phenylethoxy)-3-(S)-phenyl-4-(5tetrazolo)-methyl-morpholine;

160)2-(R)-(1-(R)-(3-Chloro)-phenylethoxy)-3-(S)-(4-fluoro)-phenyl-4-(5-tetrazolo)-methyl-morpholine;

161) 2-(S)-(3 -Chloro)benzyloxy-3 -(S)-phenyl-4-(2-oxo-5H-pyrrol-4-yl)-methyl-morpholine;

162) 2-(S)-(3-Chloro)benzyloxy-3-(S)-(4-fluoro)-phenyl-4-(2-oxo-5H-pyrrol-4-yl)-methyl-morpholine;

163) 2-(R)-(1-(R)-(3-Chloro)-phenylethoxy)-3-(S)-phenyl-4-(2-oxo-5H-pyrrol-4-yl)-methyl-morpholine;

164) 2-(R)-(1-(R)-(3-Chloro)-phenylethoxy)-3-(S)-(4-fluoro)-phenyl-4

165) 2-oxo-5H-pyrrol-4-yl)-methyl-morpholine; 1.65)2-(S)-(3-Trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(3-(1,2,4-triazolo)-methylmorpholine;

166)2-(S)-(3-Trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

167)2-(R)-(1-(R)-(3-Trifluoromethyl)-phenylethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

168)2-(R)-(1-(R)-(3-Trifluoromethyl)-phenylethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

169) 2-(S)-(3 -Trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(3 -(5-oxo-1,2,4-triazolo)-methyl-morpholine;

170) 2-(S)-(3-Trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)-phenyl-4-(3(5-oxo-1,2,4-triazolo)-methyl-morpholine;

171) 2-(R)-(I-(R)-(1-(3-(trifluoromethyl)naphthyl))ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

172) 2-(R)-(1-(R)-(3-Trifluoromethyl)-phenylethoxy)-3-(S)-(4-fluoro))-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

173)2-(S)-(3-Trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(4-(2-oxo-1,3-imidazolo)-methyl-morpholine;

174) 2-(S)-(3-Trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)-phenyl-4-(4(2-oxo-1,3-imidazolo)-methyl-morpholine;

175) 2-(R)-(1-(R)-(3-Trifluoromethyl)-phenylethoxy)-3-(S)-phenyl-4(4-(2-oxo-1,3-imidazolo)-methyl-morpholine;

176)2-(R)-(l-(R)-(3-Trifluoromethyl)-phenylethoxy)-3-(S)-(4-fluoro)-phenyl-4-(4-(2-oxo-1,3-imidazolo)-methyl-morpholine;

177) 2-(S)-(3 -Trifluoromethyl)benzyloxy-3 -(S)-phenyl-4-(2imidazolo)methyl-morpholine;

178)2-(S)-(3-Trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)-phenyl-4-(2imidazolo)-methyl-morpholine;

1796) 2-(R)-(1-(R)-(3 -Trifluoromethyl)-phenylethoxy)-3-(S)-phenyl-4(2-imidazolo)-methyl-morpholine;

180) 2-(R)-(1-(R)-(3-Trifluoromethyl)-phenylethoxy)-3-(S)-(4-fluoro))-phenyl-4-(2-imidazolo)-methyl-morpholine;

181) 2-(S)-(3 -Trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(4imidazolo)-methyl-morpholine;

182)2-(S)-(3-Trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)-phenyl-4-(4imidazolo)-methyl-morpholine;

183)2-(R)-(1-(R)-(3-Trifluoromethyl)-phenylethoxy)-3-(S)-phenyl-4(4-imidazolo)-methyl-morpholine;

184)2-(R)-(1-(R)-(3-Trifluoromethyl)-phenylethoxy)-3-(S)-(4-fluoro)-phenyl-4-(4-imidazolo)-methyl-morpholine;

185) 2-(S)-(3-Trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(5-tetrazolo)-methyl-morpholine;

186)2-(S)-(3-Trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)-phenyl-4-(5tetrazolo)-methyl-morpholine;

187) 2-(R)-(1-(R)-(3-Trifluoromethyl)-phenylethoxy)-3-(S)-phenyl-4(5-tetrazolo)-methyl-morpholine;

188) 2-(R)-(1-(R)-(3-Trifluoromethyl)-phenylethoxy)-3-(S)-(4-fluoro))-phenyl-4-(5-tetrazolo)-methyl-morpholine;

189) 2-(S)-(3 -Trifluoromethyl)benzyloxy-3-(S)-phenyl-4-(2-oxo-5 H-pyrrol-4-yl)-methyl-morpholine;

190)2-(S)-(3-Trifluoromethyl)benzyloxy-3-(S)-(4-fluoro)-phenyl-4-(2-oxo-5H-pyrrol-4-yl)-methyl-morpholine;

191)2-(R)-(1-(R)-(3-Trifluoromethyl)-phenylethoxy)-3-(S)-phenyl-4(2-oxo-5H-pyrrol-4-yl)-methyl-morpholine;

192)2-(R)-(1-(R)-(3-Trifluoromethyl)-phenylethoxy)-3-(S)-(4-fluoro)-phenyl-4-(2-oxo-5H-pyrrol-4-yl)-methyl-morpholine;

193) 2-(S)-(3-t-Butyl)benzyloxy-3-(S)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

194)2-(S)-(3-t-Butyl)benzyloxy-3-(S)-(4-fluoro)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

195)2-(R)-(1-(R)-(3-t-Butyl)-phenylethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

196)2-(R)-(1-(R)-(3-t-Butyl)-phenylethoxy)-3-(S)-(4-fluoro)-phenyl-4(3-(1,2,4-triazolo)-methyl-morpholine;

197) 2-(S)-(3-t-Butyl)benzyloxy-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

198) 2-(S)-(3-t-Butyl)benzyloxy-3-(S)-(4-fluoro)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

199) 2-(R)-(1-(R)-(3-t-Butyl)-phenylethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

200)2-(R)-(1-(R)-(3-t-Butyl)-phenylethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

201) 2-(S)-(3-t-Butyl)benzyloxy-3 -(S)-phenyl-4-(4-(2-oxo-1,3imidazolo)-methyl-morpholine;

202) 2-(S)-(3-t-Butyl)benzyloxy-3-(S)-(4-fluoro)-phenyl-4-(4-(2-oxo-1,3-imidazolo)-methyl-morpholine;

203) 2-(R)-(I -(R)-(3-t-Butyl)-phenylethoxy)-3-(S)-phenyl-4-(4-(2-oxo-1,3-imidazolo)-methyl-morpholine;

204)2-(R)-(1-(R)-(3-t-Butyl)-phenylethoxy)-3-(S)-(4-fluoro)-phenyl-4-(4-(2-oxo-1,3-imidazolo)-methyl-morpholine;

205)2-(S)-(3-t-Butyl)benzyloxy-3-(S)-phenyl-4-(2-imidazolo)-methylmorpholine:

206) 2-(S)-(3-t-Butyl)benzyloxy-3-(S)-(4-fluoro)-phenyl-4-(2imidazolo)methyl-morpholine;

207) 2-(R)-(1-(R)-(3-t-Butyl)-phenylethoxy)-3-(S)-phenyl-4-(2imidazolo)-methyl-morpholine;

208)2-(R)-(1-(R)-(3-t-Butyl)-phenylethoxy)-3-(S)-(4-fluoro)-phenyl-4-(2-imidazolo)-methyl-morpholine;

209)2-(S)-(3-t-Butyl)benzyloxy-3-(S)-phenyl-4-(4-imidazolo)-methylmorpholine;

210) 2-(S)-(3-t-Butyl)benzyloxy-3-(S)-(4-fluoro)-phenyl-4-(4imidazolo)-methyl-morpholine;

211)2-(R)-(1-(R)-(3-t-Butyl)-phenylethoxy)-3-(S)-phenyl-4-(4imidazolo)-methyl-morpholine;

212)2-(R)-(1-(R)-(3-t-Butyl)-phenylethoxy)-3-(S)-(4-fluoro)-phenyl-4-(4-imidazolo)-methyl-morpholine;

213)2-(S)-(3-t-Butyl)benzyloxy-3-(S)-phenyl-4-(5-tetrazolo)-methylmorpholine:

214)2-(S)-(3-t-Butyl)benzyloxy-3-(S)-(4-fluoro)-phenyl-4-(5-tetrazolo)-methyl-morpholine;

215)2-(R)-(1-(R)-(3-t-Butyl)-phenylethoxy)-3-(S)-phenyl-4-(5-tetrazolo)-methyl-morpholine;

216)2-(R)-(1-(R)-(3-t-Butyl)-phenylethoxy)-3-(S)-(4-fluoro)-phenyl-4-(5-tetrazolo)-methyl-morpholine;

217) 2-(S)-(3 -t-Butyl)benzyloxy-3-(S)-phenyl-4-(2-oxo-5H-pyrrol-4-yl)-methyl-morpholine;

218) 2-(S)-(3-t-Butyl) benzyloxy-3-(S)-(4-fluoro)-phenyl-4-(2-oxo-5 H-pyrrol-4-yl)-methyl-morpholine;

219) 2-(R)-(1-(R)-(3-t-Butyl)-phenylethoxy)-3-(S)-phenyl-4-(2-oxo-5H-pyrrol-4-yl)-methyl-morpholine;

220)2-(R)-(l-(R)-(3-t-Butyl)-phenylethoxy)-3-(S)-(4-fluoro)-phenyl-4-(2-oxo-5H-pyrrol-4-yl)-methyl-morpholine;

221)2-(R)-(1-(R)-(3-(thiomethylphenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

222)2-(R)-(1-(R)-(3-(thiomethylphenyl)ethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

223) 2-(R)-(1-(R)-(3 -(thiomethylphenyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

224) 2-(R)-(1-(R)-(3-(thiomethyl-5-(trifluoromethyl)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

225) 2-(R)-(1-(R)-(3-(thiomethyl-5-(trifluoromethyl)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

226) 2-(R)-(1-(R)-(3-(thiomethyl-5-(trifluoromethyl)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

227)2-(R)-(1-(R)-(2,2-(dimethyl)-5-(thiomethyl)-2,3-dihydrobenzofuran-7-yl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

228)2-(R)-(1-(R)-(2,2-(dimethyl)-5-(thiomethyl)-2,3-dihydrobenzofuran-7-yl)ethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

229)2-(R)-(1-(R)-(2,2-(dimethyl)-5-(thiomethyl)-2,3dihydrobenzofuran-7-yl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

230)2-(R)-(1-(R)-(3,5-(dimethoxy)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

231)2-(R)-(1-(R)-(3,5-(dimethoxy)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

232)2-(R)-(1-(R)-(3,5-(dimethoxy)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

233)2-(R)-(1-(R)-(3-(fluoro)-5-(trifluoromethyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

234)2-(R)-(1-(R)-(3-(fluoro)-5-(trifluoromethyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

235)2-(R)-(1-(R)-(3-(fluoro)-5-(trifluoromethyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

236)2-(R)-(1-(R)-(3-(chloro)-5-(trifluoromethyl)ethoxy)-3-(S)-(4-fluoro))-phenyl-4-(3)-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

237)2-(R)-(1-(R)-(3-(chloro)-5-(trifluoromethyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

238) 2-(R)-(1-(R)-(3-(chloro)-5-(trifluoromethyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

239)2-(R)-(1-(R)-(3,5-(dimethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

240)2-(R)-(1-(R)-(3,5-(dimethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

241)2-(R)-(1-(R)-(3,5-(dimethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

242) 2-(R)-(1-(R)-(3-(fluoro)-5-(methyl)-phenyl)ethoxy)-3-(S)-(4-fluoro))-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

243)2-(R)-(1-(R)-(3-(fluoro)-5-(methyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

244)2-(R)-(1-(R)-(3-(fluoro)-5-(methyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(2-oxo-i,3-imidazolo)-methyl-morpholine;

245) 2-(R)-(1-(R)-(3-(chloro)-5-(methyl)-phenyl)ethoxy)-3-(S)-(4-fluoro))-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

246)2-(R)-(1-(R)-(3-(chloro)-5-(methyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

247) 2-(R)-(1-(R)-(3-(chloro)-5-(methyl)-phenyl)ethoxy)-3-(S)-(4-fluoro))-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

248) 2-(R)-(1-(R)-(3-(bromo)-5-(methyl)-phenyl)ethoxy)-3-(S)-(4-fluoro))-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

249)2-(R)-(1-(R)-(3-(bromo)-5-(methyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

250)2-(R)-(1-(R)-(3-(bromo)-5-(methyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

251)2-(R)-(1-(R)-(3-(isopropoxy)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

252) 2-(R)-(1-(R)-(3-(isopropoxy)-phenyl)ethoxy)-3-(S)-(4-fluoro))-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

253)2-(R)-(1-(R)-(3-(isopropoxy)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

254) 2-(R)-(1-(R)-(3-(isopropoxy)-5-(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methylmorpholine;

255) 2-(R)-(1-(R)-(3 -(isopropoxy)-5 -(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

256) 2-(R)-(1-(R)-(3-(isopropoxy)-5-(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methylmorpholine:

257)2-(R)-(1-(R)-(3-(chloro)-5-(isopropoxy)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

258)2-(R)-(1-(R)-(3-(chloro)-5-(isopropoxy)-phenyl)ethoxy)-3-(S)-(4-fluoro))-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

259)2-(R)-(1-(R)-(3-(chloro)-5-(isopropoxy)-phenyl)ethoxy)-3-(S)-(4-fluoro))-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

260)2-(R)-(1-(R)-(3-(fluoro)-5-(isopropoxy)-phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

261)2-(R)-(1-(R)-(3-(fluoro)-5-(isopropoxy)-phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

262)2-(R)-(l-(R)-(3-(fluoro)-5-(isopropoxy)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

263)2-(R)-(1-(R)-(3-(t-butyl)-5-(chloro)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

264)2-(R)-(1-(R)-(3-(t-butyl)-5-(chloro)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

265)2-(R)-(1-(R)-(3-(t-butyl)-5-(chloro)-phenyl)ethoxy)-3-(S)-(4-fluoro))-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

266)2-(R)-(1-(R)-(3-(t-butyl)-5-(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methylmorpholine;

267)2-(R)-(1-(R)-(3-(t-butyl)-5-(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

268) 2-(R)-(1-(R)-(3-(t-butyl)-5-(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methylmorpholine;

269) 2-(R)-(1-(R)-(3,5-(dimethyl)-4-(fluoro)-phenyl)ethoxy)-3-(S)-(4-fluoro))-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

270) 2-(R)-(1-(R)-(3,5 -(dimethyl)-4-(fluoro)-phenyl)ethoxy)-3-(S)-(4-fluoro) )-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

271)2-(R)-(1-(R)-(3,5-(dimethyl)-4-(fluoro)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

272)2-(R)-(1-(R)-(3,5-(dimethyl)-4-(chloro)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

273)2-(R)-(1-(R)-(3,5-(dimethyl)-4-(chloro)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

274)2-(R)-(1-(R)-(3,5-(dimethyl)-4-(chloro)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

275) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-4-(fluoro)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methylmorpholine;

276) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-4-(fluoro)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

277) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-4-(fluoro)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methylmorpholine;

278) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-4-(chloro)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methylmorpholine;

279) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-4-(chloro)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

280) 2-(R)-(1-(R)-(3 ,5-bis(trifluoromethyl)-4-(chloro)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methylmorpholine:

281) 2-(R)-(1-(R)-(3,5-(dichloro)-phenyl)ethoxy)-3-(S)-(4-fluoro))-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

282) 2-(R)-(1-(R)-(3,5-(dichloro)-phenyl)ethoxy)-3-(S)-(4-fluoro))-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

283)2-(R)-(1-(R)-(3,5-(dichloro)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

284) 2-(R)-(1-(R)-(3,5-(difluoro)-phenyl)ethoxy)-3-(S)-(4-fluoro))-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

285)2-(R)-(1-(R)-(3,5-(difluoro)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

286) 2-(R)-(1-(R)-(3,5-(difluoro)-phenyl)ethoxy)-3-(S)-(4-fluoro))-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

287)2-(R)-(1-(R)-(1-(naphthyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

288)2-(R)-(1-(R)-(1-(naphthyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

289)2-(R)-(1-(R)-(1-(naphthyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

290) 2-(R)-(1-(R)-(1-(4-(fluoro)naphthyl))ethoxy)-3-(S)-(4-fluoro))-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

291) 2-(R)-(1-(R)-(1-(4-(fluoro)naphthyl))ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

292) 2-(R)-(1-(R)-(1-(4-(fluoro)naphthyl))ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

293)2-(R)-(I-(R)-(1-(3-(fluoro)naphthyl))ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

294) 2-(R)-(I -(R)-(1-(3-(fluoro)naphthyl))ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

295) 2-(R)-(1-(R)-(1-(3-(fluoro)naphthyl))ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

296)2-(R)-(I-(R)-(1-(3-(chloro)naphthyl))ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

297)2-(R)-(I-(R)-(1-(3-(chloro)naphthyl))ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

298)2-(R)-(I-(R)-(1-(3-(chloro)naphthyl))ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

299) 2-(R)-(1-(R)-(1-(3-(methyl)naphthyl))ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

300) 2-(R)-(1-(R)-(1-(3-(methyl)naphthyl))ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

301)2-(R)-(I-(R)-(1-(3-(methyl)naphthyl))ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

302)2-(R)-(I-(R)-(1-(3-(trifluoromethyl)naphthyl))ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

303)2-(R)-(1-(R)-(l-(3-(trifluoromethyl)naphthyl))ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

304)2-(R)-(1-(R)-(1-(3-(trifluoromethyl)naphthyl))ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

305)2-(R)-(1-(R)-(3-(thiomethylphenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

306) 2-(R)-(1-(R)-(3-(thiomethylphenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

307) 2-(R)-(1-(R)-(3-(thiomethylphenyl)ethoxy)-3-(S)-(4-fluoro))-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

308) 2-(R)-(1-(R)-(3-(thiomethyl-5-(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methylmorpholine;

309) 2-(R)-(1-(R)-(3-(thiomethyl-5-(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(l,2,4-triazolo)-methyl-morpholine;

310) 2-(R)-(1-(R)-(3-(thiomethyl-5-(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methylmorpholine;

311)2-(R)-(1-(R)-(2,2-(dimethyl)-5-(thiomethyl)-2,3-dihydrobenzofuran-7-yl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

312)2-(R)-(1-(R)-(2,2-(dimethyl)-5-(thiomethyl)-2,3-dihydrobenzofuran-7-yl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

313)2-(R)-(1-(R)-(2,2-(dimethyl)-5-(thiomethyl)-2,3-dihydrobenzofuran-7-yl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3 -(2-oxo-1,3-imidazolo)-methyl-morpholine;

314)2-(R)-(1-(R)-(3,5-(dimethoxy)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

315)2-(R)-(1-(R)-(3,5-(dimethoxy)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

316) 2-(R)-(1-(R)-(3,5-(dimethoxy)-phenyl)ethoxy)-3-(S)-(4-fluoro))-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

317)2-(R)-(1-(R)-(phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

318) 2-(R)-(1-(R)-(phenyl)ethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

319)2-(R)-(1-(R)-(phenyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3imidazolo)-methyl-morpholine;

320)2-(R)-(1-(R)-(phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

321)2-(R)-(1-(R)-(phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

322)2-(R)-(1-(R)-(phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

323)2-(R)-(1-(R)-(3-(fluoro)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

324)2-(R)-(1-(R)-(3-(fluoro)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

325)2-(R)-(1-(R)-(3-(fluoro)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

326)2-(R)-(1-(R)-(3-(fluoro)-phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

327)2-(R)-(1-(R)-(3-(fluoro)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

328)2-(R)-(1-(R)-(3-(fluoro)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

329)2-(R)-(1-(R)-(4-(fluoro)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

330) 2-(R)-(1-(R)-(4-(fluoro)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

331)2-(R)-(1-(R)-(4-(fluoro)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

332)2-(R)-(1-(R)-(4-(fluoro)-phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

332)2-(R)-(1-(R)-(4-(fluoro)-phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

333)2-(R)-(1-(R)-(4-(fluoro)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

334)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(3-fluoro)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

335)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(3-fluoro)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

336)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(3-fluoro)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

337)2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(3,4-difluoro)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

338)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(3,4-difluoro)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

339)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(3,4-difluoro)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

340)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(3,4-dichloro)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

341)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(3,4-dichloro)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

342)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(3,4-dichloro)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-:morpholine;

343) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(3,4-dimethyl)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

344) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(3,4-dimethyl)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

345)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(3,4-dimethyl)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

346)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-3,4-methylenedioxyphenyl-4-(3-(5-oxo-1,2,4-triazolo)-methylmorpholine;

347)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-3,4-methylenedioxyphenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

348)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-3,4-methylenedioxyphenyl-4-(3-(2-oxo-1,3-imidazolo)-methylmorpholine;

349)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(2-naphthyl)-4-(3-(5-oxo-1,2,4-triazolo)-methyl-morpholine;

350)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(2-naphthyl)-4-(3-(1,2,4-triazolo)-methyl-morpholine;

351)2-(R)-(I-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(2-naphthyl)-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

352) 2-(R)-(1-(R)-(3-(fluoro)-5-(trifluoromethyl)ethoxy)-3-(S)-phenyl-4-(3-(-1,2,4-triazolo)-methyl-morpholine;

353) 2-(R)-(1-(R)-(3-(fluoro)-5-(trifluoromethyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

354) 2-(R)-(1-(R)-(3-(chloro)-5-(trifluoromethyl)ethoxy)-3-(S)-phenyl-4-(3-(-1,2,4-triazolo)-methyl-morpholine;

355) 2-(R)-(1-(R)-(3-(chloro)-5-(trifluoromethyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

356)2-(R)-(1-(R)-(3,5-(dimethyl)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine:

357)2-(R)-(1-(R)-(3,5-(dimethyl)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

358) 2-(R)-(1-(R)-(3-(fluoro)-5-(methyl)-phenyl)ethoxy)-3-(S)-phenyl-(3-(-1,2,4-triazolo)-methyl-morpholine;

359) 2-(R)-(1-(R)-(3-(fluoro)-5-(methyl)-phenyl)ethoxy)-3-(S)-phenyl-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

360) 2-(R)-(1-(R)-(3-(chloro)-5-(methyl)-phenyl)ethoxy)-3-(S)-phenyl-(3-(-1,2,4-triazolo)-methyl-morpholine;

361) 2-(R)-(1-(R)-(3-(chloro)-5-(methyl)-phenyl)ethoxy)-3-(S)-phenyl-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

362) 2-(R)-(1-(R)-(3-(bromo)-5-(methyl)-phenyl)ethoxy)-3-(S)-phenyl-(3-(-1,2,4-triazolo)-methyl-morpholine;

363) 2-(R)-(1-(R)-(3-(bromo)-5-(methyl)-phenyl)ethoxy)-3-(S)-phenyl-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

364)2-(R)-(1-(R)-(3-(isopropoxy)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

365) 2-(R)-(1-(R)-(3-(isopropoxy)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

366) 2-(R)-(I -(R)-(3 -(isopropoxy)-5-(trifluoromethyl)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(-1,2,4-triazolo)-methyl-morpholine;

367) 2-(R)-(1-(R)-(3-(isopropoxy)-5-(trifluoromethyl)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

368) 2-(R)-(1-(R)-(3-(chloro)-5-(isopropoxy)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(-1,2,4-triazolo)-methyl-morpholine;

369) 2-(R)-(1-(R)-(3 -(chloro)-5-(isopropoxy)-phenyl)ethoxy)-3 -(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

370) 2-(R)-(1-(R)-(3-(fluoro)-5-(isopropoxy)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(-1,2,4-triazolo)-methyl-morpholine;

371) 2-(R)-(1-(R)-(3-(fluoro)-5-(isopropoxy)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

372) 2-(R)-(1-(R)-(3-(t-butyl)-5-(chloro)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(-1,2,4-triazolo)-methyl-morpholine;

373) 2-(R)-(1-(R)-(3-(t-butyl)-5-(chloro)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

374)2-(R)-(1-(R)-(3-(t-butyl)-5-(trifluoromethyl)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(-1,2,4-triazolo)-methyl-morpholine;

375)2-(R)-(1-(R)-(3-(t-butyl)-5-(trifluoromethyl)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

376) 2-(R)-(1-(R)-(3,5-(dimethyl)-4-(fluoro)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(-1,2,4-triazolo)-methyl-morpholine;

377) 2-(R)-(l-(R)-(3,5-(dimethyl)-4-(fluoro)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

378) 2-(R)-(1-(R)-(3,5-(dimethyl)-4-(chloro)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(-1,2,4-triazolo)-methyl-morpholine;

379) 2-(R)-(1-(R)-(3,5-(dimethyl)-4-(chloro)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

380) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-4-(fluoro)-phenyl)ethoxy) -3-(S)-phenyl-4-(3 -(-1,2,4-triazolo)-methyl-morpholine;

381) 2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)-4-(fluoro)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

382) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-4-(chloro)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(-1,2,4-triazolo)-methyl-morpholine;

383) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-4-(chloro)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

384)2-(R)-(1-(R)-(3,5-(dichloro)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

385)2-(R)-(1-(R)-(3,5-(dichloro)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

386)2-(R)-(1-(R)-(3,5-(difluoro)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

387)2-(R)-(1-(R)-(3,5-(difluoro)-phenyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

388) 2-(R)-(1-(R)-(1-(naphthyl)ethoxy)-3-(S)-phenyl-4-(3-(1,2,4-triazolo)-methyl-morpholine;

389)2-(R)-(1-(R)-(1-(naphthyl)ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3imidazolo)-methyl-morpholine;

390)2-(R)-(I-(R)-(1-(4-(fluoro)naphthyl))ethoxy)-3-(S)-phenyl-4-(3-(-1,2,4-triazolo)-methyl-morpholine;

391) 2-(R)-(1-(R)-(1-(4-(fluoro)naphthyl))ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

392) 2-(R)-(1-(R)-(1-(3-(fluoro)naphthyl))ethoxy)-3-(S)-phenyl-4-(3-(-1,2,4-triazolo)-methyl-morpholine;

393) 2-(R)-(1-(R)-(1-(3-(fluoro)naphthyl) )ethoxy)-3-(S)-phenyl-4-(2-oxo-1,3-imidazolo)-methyl-morpholine;

394)2-(R)-(1-(R)-(1-(3-(chloro)naphthyl))ethoxy)-3-(S)-phenyl-4-(3-(-1,2,4-triazolo)-methyl-morpholine;

395) 2-(R)-(1-(R)-(1-(3-(chloro)naphthyl))ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine;

396)2-(R)-(I-(R)-(1-(3-(methyl)naphthyl))ethoxy)-3-(S)-phenyl-4-(3-(-1,2,4-triazolo)-methyl-morpholine;

397) 2-(R)-(1-(R)-(1-(3-(methyl)naphthyl))ethoxy)-3-(S)-phenyl-4-(3-(2-oxo-1,3-imidazolo)-methyl-morpholine.

EXAMPLE 882-(R)-(2,5-Bis(trifluoromethyl)benzoyloxy)-3-(S)-(4-fluorophenyl)-4-benzyl-morpholine

The title compound was prepared from3-(S)-(4-fluorophenyl)-4-benzyl-2-morpholinone (from Example 59) using aprocedure analogous to Example 67.

Mass Spectrum (Cl): m/Z 528 (M+H)

¹ H NMR (CDCl₃, 360 MHz, ppm): δ2.46 (dt, 1H), 2.90 (dd, 2H), 3.76 (dd,J=11.6, 2.0, 1H), 3.88 (d, J=13.6, 1H), 4.18 (t, 1H), 6.20 (d, J=2.8,1H), 7.04 (d, J=8.4, 2H), 7.24-7.32 (m, 5H), 7.50, (m, 2H), 7.60 (s,1H), 7.88 (dd, 2H).

EXAMPLE 892-(R)-(1-(2,5-Bis(trifluoromethyl)-phenyl)ethenyloxy)-3-(S)-(4-fluorophenyl)-4-benzyl-morpholine

The title compound was prepared from 2-(R)-(2,5bis(trifluoromethyl)benzoyloxy)-3-(S)-(4-fluorophenyl)-4-benzylmorpholine (from Example 88)using a procedure analogous to Example 68.

¹ H NMR (CDCl₃, 250 MHz, ppm): δ2.30 (dt, J=3.5, 11.9, 1H), 2.74 (app d,J=9.4, 1H), 2.82 (d, J=13.5, 1H), 3.55-3.60 (m, 2H), 3.72 (d, J=13.5,1H), 4.10 (dt, J=2.4, 11.7, 1H), 4.22 (d, J=2.7, 1H), 4.67 (d,J=2.8.1H), 5.18 (d, J=2.8, 1H), 6.90 (t, J=8.7, 2H), 7.08 (s, 1H),7.13-7.23 (m, 5H), 7.36 (dd, J=5.6, 8.7, 2H). 7.62 (d, J=8.4, 1H), 7.72(d, J=8.4. 1H).

EXAMPLE 902-(R)-(1-(R)-(2,5-Bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-morpholine

The title compound was prepared from 2-(R)-(1-(2,5-bis(trifluoromethyl)phenyl)ethenyloxy)-3-(S)-(4-fluorophenyl)-4-benzyl-morpholine (fromExample 89) using a procedure analogous to Example 74.

Mass Spectrum (Cl): m/Z 438 (M+H)

¹ H NMR Spectrum (HCl salt, d6-DMSO, 360 MHz, ppm): δ1.47 (d, J=8.7,3H), 3.88 (d, J=11.8, 1H), 4.20 (dt, J=3.7, 11.8, 1H), 4.50 (s, 1H),4.58 (s, 1H), 5.17 (m, 1H), 7.04 (s, 1 H), 7.23 (t, J=8.8, 2H), 7.55 (m,2H), 7.77 (d, J=8.1, 1H), 7.88 (d, J=8.3, 1H), 10.1 (br s, 1H).

EXAMPLE 912-(R)-(1-(R)-(2,5-Bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1,2,4-triazolo)-methylmorpholine

The title compound was prepared from2-(R)-(1-(R)-(2,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-morpholine(from Example 90) using a procedure analogous to Example 70, mp162°-168° C.

¹ H NMR (d6-DMSO, 360 MHz, ppm) δ1.37 (d, J=6.4, 3H), 2.40 (dt, J=3.3,11.9, 1H), 2.77 (d, J=14.0, 1H), 2.86 (d, J=11.5, 1H), 3.37 (d, J=14.4,1H), 3.48 (d, J=2.7, 1H), 3.64 (d, J=11.0, 1H), 4.11 (t, J=9.8, 1H),4.18 (d, J=2.8, 1H), 5.16 (q, J=6.2, 1H), 6.90 (s, 1H), 7.08 (t, J=8.8,2H), 7.50 (br t, 1 H), 7.74 (d, J=8.3, 1 H), 7.85 (d, J=8.3, 1H), 11.25s, 1H), 11.35 (s, 1H).

EXAMPLE 922-(R)-(1-(R)-(2,5-Bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(1,2,4-triazolo)-methyl)morpholine

The title compound was prepared from2-(R)-(1-(R)-(2,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-morpholine(from Example 90) using a procedure analogous to Example 17, mp 98°-100°C.

Mass Spectrum (Cl): m/Z 519 (M+H)

¹ H NMR (d6-DMSO, 360 MHz, ppm): δ1.36 (d, J=6.4, 3H), 2.46 (dt, J=3.26,11.9, 1H), 2.89 (d, J=11.0, 1H), 3.16 (d, J=13.9, 1H), 3.57-3.64 (m,3H), 4.09 (t, J=10.5, 1H), 4.18 (d, J=2.6, 1H), 5.14 (q, J=6.4, 1H),6.90 (s, 1 H), 7.11 (t, J=8.7, 2H), 7.48 (m, 2H), 7.72 (d, J=8.3, 1H),7.83 (d, J=8.3, 1H), 8.36 (br s), 13.8 (s, 1H).

EXAMPLE 932-(R)-(1-(R)-(2,5-Bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-(2-oxo-1.3-imidazolo)-methyl)morpholine

The title compound was prepared from2-(R)-(1-(R)-(2,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-morpholine (from Example 90) using a procedureanalogous to Example 83. A sample was recrystallized from aqueousethanol, mp 203°-205° C.

¹ H NMR (d6-DMSO, 360 MHz, ppm): δ1.35 (d, J=6.4, 3H), 2.25 (dt, J=3.1,11.8, 1H), 2.58 (d, J=13.9, 1H), 2.88 (d, J=11.6, 1H), 3.24 (d, J=14.0,1H), 3.35 (d, J=2.7, 1 H), 3.64 (dd, J=9.6, 1H), 4.09 (t, J=9.8, 1H),4.16 (d, J=2.7, 1H), 5.14 (q, J=6.5, 1 H), 5.97 (s, 1H), 6.89 (s, 1H),7.07 (t, J=8.7, 1H), 7.49 (m, 1 H), 7.72 (d, J=8.1, 1H), 7.83 (d, J=8.3,1H), 9.57 (s, 1H), 9.80 (s, 1H).

EXAMPLE 942-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-4-(3-(5-oxo-1H.4H-1,2,4-triazolo)-methyl)morpholine N-oxide

A solution of 125 mg (0.25 mmol) of 2-(S)-(3,5bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)-methylmorpholinein 10 mL of methylene chloride was treated with 100 mg of 80-85%3-chloroperoxybenzoic acid and the resulting mixture was stirred at roomtemperature for 1 hour. The reaction mixture was concentrated in vacuoand the residue was partitioned between 25 mL of ethyl acetate and 25 mLof saturated aqueous sodium bicarbonate solution. The organic layer wasseparated, washed with 15 mL of 0.1 N aqueous sodium hydroxide solution,dried over sodium sulfate and concentrated in vacuo to afford 142 mg ofcrude product. Flash chromatography on silica gel (15 mL column) using95:5:0.5 v/v/v methylene chloride/methanol/water as the eluant afford 83mg (64%) of the title compound.

Mass Spectrum (NH₃ -CI): m/Z 519 (20%, M⁺), 406 (90%), 404 (100%).

¹ H NMR (CDCl₃, 500 MHz, ppm): δ3.56-3.66 (m, 1H), 3.80 (br d, J=10.0,1H), 3.95-4.20 (m, 3H), 4.43-4.47 (m, 1H), 4.50 (d, J=13.4, 1H),4.86-4.94 (m, 3H), 7.32 (app s, 5H), 7.56 (s, 2H), 7.68 (s, 1 H), 8.40(br s, 1H) 12.15 (br s, 1H).

EXAMPLE 95 2-(S)-(3,5 -Bis (trifluoromethyl)benzyloxy)-3-(S)-phenyl-4-(3-(4-(ethoxycarbonyloxy-1-ethyl)5-oxo-1H,-1,2,4-triazolo)-methyl)morpholine

A mixture of 250 mg (0.5 mmol) of 2-(S)-(3,5bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)-methylmorpholine,70 mg (0.5 mmol) of N,N-diisopropylethylamine and 100mg(1-chloroethyl)ethylcarbonate in 15 mL of dichloroethane was heated atreflux for 16 hours. TLC analysis of the reaction mixture indicatedincomplete reaction; the dichloroethane solvent was replaced withtoluene, 70 mg of N,N-diisopropylethylamine and 100 mg(1-chloroethyl)ethylcarbonate were added to the reaction and theresulting mixture was heated at reflux for 24 hours. At this time, anadditional 70 mg of N,N-diisopropylethylamine and 100 mg(1chloroethyl)ethylcarbonate were introduced into the reaction and the resultingmixture was heated at reflux for 24 hours. The reaction was cooled toroom temperature and partitioned between 25 mL of ethyl acetate and 25mL of saturated aqueous sodium bicarbonate solution and the layers wereseparated. The aqueous layer was extracted with ethyl acetate. Theorganic layers were combined, dried over sodium sulfate and concentratedin vacuo to afford 420 mg of crude product as a foam. Flashchromatography on silica gel (25 mL column) using 100:1 v/v, then 50:1v/v methylene chloride/isopropanol as the eluant afforded 68 mg (22%) ofthe title compound.

Mass Spectrum (ESI): m/Z 619 (15%, M+I), 575 (100%).

¹ H NMR (CDCl₃, 500 MHz, ppm): δ1.38 (t, J=7.0, 3H), 2.61 (dt, J=3.0.12.0, 1H), 2.90 (d, J=11.5, 1H), 3.03 (d, J=15.5, 1H), 3.63 (d, J=2.0,1H), 3.66-3.71 (m, 2H), 4.20 (dt, J=2.0, 11.5, 1H), 4.41-4.45 (m, 2H),4.48 (d, J=13.5, 1H), 4.71 (d, J=2.0, 1H), 4.81 (d, J=13.5, 1H),7.34-7.48 (m, 5H), 7.47 (s, 2H), 7.72 (s, 1H), 10.1 (br s, 1H).

¹³ C NMR (CDCl₃, 125 MHz, ppm): δ14.2, 25.2, 50.7, 52.6, 59.2, 64.1,64.5, 67.7, 69.7, 97.9, 121.5, 123.1 (q, J=27 1), 127.2, 128.7, 129.1,131.5 (q, J=32.9), 136.0, 140.0, 146.8, 148.4, 152.3, 163.1.

EXAMPLE 962-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(4-monophosphoryl-5-oxo-1H,-1,2,4-triazolo)-methyl)morpholine,dipotassium salt; or 2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(1-mono-phosphoryl-5-oxo-1H,-1,2,4-triazolo)-methyl)morpholine, dipotassiumsalt; or2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(2-monophosphoryl-5-oxo-1H,-1,2,4-triazolo)-methyl)morpholine,dipotassium salt; or2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(5-oxyphosphoryl-1H,-1,2,4,-triazolo)-methyl)morpholine,dipotassium salt

A solution of 450 mg (0.84 mmol) of2-(R)-(1-(R)-(3,5-bis(trifluoro-methyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(5-oxo-1H, 4H-1,2,4-triazolo) methylmorpholine in 20 mL of THF at 0° C. wastreated with 0.84 mL of 1.0 N n-butyllithium solution in hexanes. Theresulting solution was stirred cold for 5 minutes and was treated with630 mg(1.17 mmol) of tetrabenzylpyrophosphate in one portion as a solid.The cooling bath was removed and the reaction was stirred at roomtemperature for 45 minutes. The reaction was quenched with 25 mL ofsaturated aqueous sodium bicarbonate solution and was extracted with 50mL of ethyl ether. The organic layer was separated, washed with 25 mL ofsaturated aqueous sodium bicarbonate solution, 25 mL of 0.5 N aqueouspotassium hydrogen sulfate solution, 25 mL of saturated aqueous sodiumchloride solution, dried over magnesium sulfate and concentrated invacuo. The crude dibenzyl ester was dissolved in 25 mL of methanol. Asolution of 168 mg (1.68 mmol) of potassium bicarbonate was added to theester solution and the resulting mixture was hydrogenated at 40 psi inthe presence of 45 mg of 10% palladium on carbon catalyst for 75minutes. The catalyst was filtered onto a pad of Celite; the reactionflask and filter cake were rinsed well with methanol (-200 mL), thefiltrate was concentrated in vacuo and dried. The residue was partiallydissolved in methanol and filtered; the filtrate was concentrated anddried. The resulting solid was recrystallized from isopropanol to afford280 mg of crude title compound. The solid was partitioned between 40 mLof ethyl ether and 20 mL of water; mixing of the layers resulted in anemulsion. Centrifugation at 2800 rpm for 15 minutes broke the emulsion;the aqueous layer was separated and lyophilized to afford 188 mg (33%)of the compound tentatively identified as2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(4-monophosphoryl-5-oxo-1H,-1,2,4-triazolo)-methyl)-morpholine, dipotassium salt as a solid.

¹ H NMR (CD₃ OD, 500 MHz, ppm): δ1.43 (d, J=6.5, 3H), 2.45 (app t,J=8.5, 1H), 2.80 (d, J=14.0, 1H), 2.92 (d, J=11.5, 1H), 3.47-3.66 (m,4H), 4.25 (app t, J=11.5, 1H), 4.36 (d, J=1.5, 1H), 4.94 (q, J=6.6, 1H),7.05 (t, J=8.5, 2H), 7.31(s, 2H), 7.52 (br s, 2H), 7.71 (s, 1H). ¹³ CNMR (CD3OD, 125 MHz, ppm): δ5 24.7, 52.3, 53.4, 60.5, 70.6, 73.7, 97.2,116.1 (d, J=21.9), 122.3, 124.6 (q, J=271.0), 127.7, 132,3, 132.6,132.8, 134.3, 145.2 (d, J=l 1.0), 147.5, 159.0 (d, J=10.1), 164.0 (d,J=244.4).

EXAMPLE 97 Typical Pharmaceutical Compositions Containing a Compound ofthe Invention A: Dry Filled Capsules Containing 50 mg of ActiveIngredient Per Capsule

    ______________________________________    Ingredient     Amount per capsule (mg)    ______________________________________    Active ingredient                    50    Lactose        149    Magnesium stearate                    1    Capsule (size No. 1)                   200    ______________________________________

The active ingredient may be reduced to a No. 60 powder and the lactoseand magnesium stearate may then be passed through a No. 60 blottingcloth onto the powder. The combined ingredients may then be mixed forabout 10 minutes and filled into a No. 1 dry gelatin capsule.

B: Tablet

A typical tablet would contain the active ingredient (25 mg),pregelatinized starch USP (82 mg), microcrystalline cellulose (82 mg)and magnesium stearate (1 mg).

C: Suppository

Typical suppository formulations for rectal administration contain theactive ingredient (1.0-100 mg), disodium calcium edetate (2.5-5.0 mg),and polyethylene glycol (775-1600 mg). Other suppository formulationsmay be made by substituting, for example, butylated hydroxytoluene(0.4-0.8 mg) for the disodium calcium edetate and a hydrogenatedvegetable oil (675-1400 mg) such as Suppocire L, Wecobee FS, Wecobee M,Witepsols, and the like, for the polyethylene glycol.

D: Injection

A typical injectible formulation contains the active ingredient, sodiumphosphate dibasic anhydrous (11.4 mg), benzyl alcohol (0.01 ml) andwater for injection (1.0 ml).

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention.For example, effective dosages other than the particular dosages as setforth herein above may be applicable as a consequence of variations inthe responsiveness of the mammal being treated for any of theindications with the compounds of the invention indicated above.Likewise, the specific pharmacological responses observed may varyaccording to and depending upon the particular active compounds selectedor whether there are present pharmaceutical carriers, as well as thetype of formulation and mode of administration employed, and suchexpected variations or differences in the results are contemplated inaccordance with the objects and practices of the present invention. Itis intended, therefore, that the invention be defined by the scope ofthe claims which follow and that such claims be interpreted as broadlyas is reasonable.

What is claimed is:
 1. A method for the treatment or prevention ofemesis in a mammal in need thereof which comprises the administration tothe mammal of an effective amount of a compound of the formula I:##STR11## or a pharmaceutically acceptable salt thereof, wherein: R² andR³ are independently selected from the group consisting of:(1) hydrogen,(2) C₁₋₆ alkyl, unsubstituted or substituted with one or ed from:(a)hydroxy, (b) oxo, (c) C₁₋₆ alkoxy, (d) phenyl --C₁₋₃ alkoxy, (e) phenyl,(f) --CN, (g) halo, (h) --NR⁹ R¹⁰, wherein R⁹ and R¹⁰ are independentlyselected from:(i) hydrogen, (ii) C₁₋₆ alkyl, (iii) hydroxy --C₁₋₆ alkyl,and (iv) phenyl, (i) --NR⁹ COR¹⁰, wherein R⁹ and R¹⁰ are as definedabove, (j) --NR⁹ CO₂ R¹⁰, wherein R⁹ and R¹⁰ are as defined above, (k)--CONR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above, (l) --COR⁹,wherein R⁹ is as defined above, and (m) --CO₂ R⁹, wherein R⁹ is asdefined above; (3) C₂₋₆ alkenyl, unsubstituted or substituted with oneor more of the substituent(s) selected from:(a) hydroxy, (b) oxo, (c)C₁₋₆ alkoxy, (d) phenyl --C₁₋₃ alkoxy, (e) phenyl, (f) --CN, (g) halo,(h) --CONR⁹ R¹⁰ wherein R⁹ and R¹⁰ are as defined above, (i) --COR⁹wherein R⁹ is as defined above, (j) --CO₂ R⁹, wherein R⁹ is as definedabove; (4) C₂₋₆ alkynyl; (5) phenyl, unsubstituted or substituted withone or more of the substituent(s) selected from:(a) hydroxy, (b) C₁₋₆alkoxy, (c) C₁₋₆ alkyl, (d) C₂₋₅ alkenyl, (e) halo, (f) --CN, (g) --NO₂,(h) --CF₃, (i) --(CH₂)_(m) -NR⁹ R¹⁰, wherein m, R⁹ and R¹⁰ are asdefined above, (j) --NR⁹ COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,(k) --NR⁹ CO₂ R¹⁰, wherein R⁹ and R¹⁰ are as de fined above, (l) --CONR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above, (m) --CO₂ NR⁹ R¹⁰, whereinR⁹ and R¹⁰ are as defined above, (n) --COR⁹, wherein R⁹ is as definedabove; (o) --CO₂ R⁹, wherein R⁹ is as defined above;and, alternatively,the groups R² and R³ are joined together to form a carbocyclic ringselected from the group consisting of: (a) cyclopentyl, (b) cyclohexyl,(c) phenyl, and wherein the carbocyclic ring is unsubstituted orsubstituted with one or more substituents selected from:(i) C₁₋₆ alkyl,(ii) C₁₋₆ alkoxy, (iii) --NR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as definedabove, (iv) halo, and v) trifluoromethyl;and, alternatively, the groupsR² and R³ are joined together to form a heterocyclic ring selected fromthe group consisting of: (a) pyrrolidinyl, (b) piperidinyl, (c)pyrrolyl, (d) pyridinyl, (e) imidazolyl, (f) furanyl, (g) oxazolyl, (h)thienyl, and (i) thiazolyl, and wherein the heterocyclic ring isunsubstituted or substituted with one or more substituent(s) selectedfrom:(i) C₁₋₆ alkyl, (ii) oxo, (iii) C₁₋₆ alkoxy, (iv) -NR⁹ R¹⁰, whereinR⁹ and R¹⁰ are as defined above, (v) halo, and (vi) trifluoromethyl:R⁶,R⁷ and R⁸ are independently selected from the group consisting of: (1)hydrogen; (2) C₁₋₆ alkyl unsubstituted or substituted with one or moreof the substituents selected from:(a) hydroxy, (b) oxo, (c) C₁₋₆ alkoxy,(d) phenyl -C₁₋₃ alkoxy, (e) phenyl, (f) -CN, (g) halo, (h) -NR⁹ R¹⁰,wherein R⁹ and R¹⁰ are as defined above, (i) -NR⁹ COR¹⁰, wherein R⁹ andR¹⁰ are as defined above, (j) -NR⁹ CO₂ R¹⁰, wherein R⁹ and R¹⁰ are asdefined above, (k) -CONR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above,(l) -COR⁹, wherein R⁹ is as defined above, and (m) -CO₂ R⁹, wherein R⁹is as defined above; (3) C₂₋₆ alkenyl, unsubstituted or substituted withone or more of the substituent(s) selected from:(a) hydroxy, (b) oxo,(c) C₁₋₆ alkoxy, (d) phenyl -C₁₋₃ alkoxy, (e) phenyl, (f) -CN, (g) halo,(h) -CONR⁹ R¹⁰ wherein R⁹ and R¹⁰ are as defined above, (i) -COR⁹wherein R⁹ is as defined above, (j) -CO₂ R⁹, wherein R⁹ is as definedabove; (4) C₂₋₆ alkynyl; (5) phenyl, unsubstituted or substituted withone or more of the substituent(s) selected from:(a) hydroxy, (b) C₁₋₆alkoxy, (c) C₁₋₆ alkyl, (d) C₂₋₅ alkenyl, (e) halo, (f) -CN, (g) -NO₂,(h) -CF₃, (i) -(CH₂)_(m) -NR⁹ R¹⁰, wherein m, R⁹ and R¹⁰ are as definedabove, (j) -NR⁹ COR¹⁰, wherein R⁹ and R¹⁰ are as defined above, (k) -NR⁹CO₂ R¹⁰, wherein R⁹ and R¹⁰ are as defined above, (l) -CONR⁹ R¹⁰,wherein R⁹ and R¹⁰ are as defined above, (m) -CO₂ NR⁹ R¹⁰, wherein R⁹and R¹⁰ are as defined above, (n) -COR⁹, wherein R⁹ is as defined above;(o) -CO₂ R⁹, wherein R⁹ is as defined above; (6) halo, (7) -CN, (8)-CF₃, (9) -NO₂, (10) -SR¹⁴, wherein R¹⁴ is hydrogen or C₁₋₅ alkyl, (11)-SOR¹⁴, wherein R¹⁴ is as defined above, (12) -SO₂ R¹⁴, wherein R¹⁴ isas defined above, (13) NR⁹ COR¹⁰, wherein R⁹ and R¹⁰ are as definedabove, (14) CONR⁹ COR¹⁰, wherein R⁹ and R¹⁰ are as defined above, (15)NR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above, (16) NR⁹ CO₂ R¹⁰,wherein R⁹ and R¹⁰ are as defined above, (17) hydroxy, (18) C₁₋₆ alkoxy,(19) COR⁹, wherein R⁹ is as defined above, (20) CO₂ R⁹, wherein R⁹ is asdefined above, (21) 2-pyridyl, (22) 3-pyridyl, (23) 4-pyridyl, (24)5-tetrazolyl, (25) 2-oxazolyl, and (26) 2-thiazolyl;R¹¹, R¹² and R¹³ areindependently selected from the definitions of R⁶, R⁷ and R⁸, or -OX; Ais selected from the group consisting of: (1) C₁₋₆ alkyl, unsubstitutedor substituted with one or more of the substituents selected from:(a)hydroxy, (b) oxo, (c) C₁₋₆ alkoxy, (d) phenyl -C₁₋₃ alkoxy, (e) phenyl,(f) -CN, (g) halo, wherein halo is fluoro, chloro, bromo or iodo, (h)-NR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above, (i) -NR⁹ COR¹⁰,wherein R⁹ and R¹⁰ are as defined above, (j) -NR⁹ CO₂ R¹⁰, wherein R⁹and R¹⁰ are as defined above. (k) -CONR⁹ R¹⁰, wherein R⁹ and R¹⁰ are asdefined above, (l) -COR⁹, wherein R⁹ is as defined above, and (m) -CO₂R⁹, wherein R⁹ is as defined above; (2) C₂₋₆ alkenyl, unsubstituted orsubstituted with one or more of the substituent(s) selected from:(a)hydroxy, (b) oxo, (c) C₁₋₆ alkoxy, (d) phenyl -C₁₋₃ alkoxy, (e) phenyl,(f) -CN, (g) halo, (h) -CONR⁹ R¹⁰ wherein R⁹ and R¹⁰ are as definedabove, (i) -COR⁹ wherein R⁹ is as defined above, and (j) -CO₂ R⁹,wherein R⁹ is as defined above; and (3) C₂₋₆ alkynyl;B is a heterocycle,wherein the heterocycle is selected from the group consisting of:##STR12## and wherein the heterocycle is substituted in addition to -Xwith one or more substituent(s) selected from: (i) hydrogen; (ii) C₁₋₆alkyl, unsubstituted or substituted with halo. -CF₃, -OCH₃, or phenyl,(iii) C₁₋₆ alkoxy, (iv) OXO, (v) hydroxy, (vi) thioxo, (vii)-SR⁹,wherein R⁹ is as defined above, (viii) halo, (ix) cyano, (x) phenyl,(xi) trifluoromethyl, (xii) -(CH₂)_(m) -NR⁹ R¹⁰, wherein m is 0, 1 or 2,and R⁹ and R¹⁰ are as defined above, (xiii) -NR⁹ COR¹⁰, wherein R⁹ andR¹⁰ are as defined above, (xiv) -CONR⁹ R¹⁰, wherein R⁹ and R¹⁰ are asdefined above, (xv) -CO₂ R⁹, wherein R⁹ is as defined above, and (xvi)-(CH₂)_(m) -OR⁹, wherein m and R⁹ are as defined above; p is 0 or 1; Xis selected from:(a) -PO(OH)O-. M⁺, wherein M⁺ is a pharmaceuticallyacceptable monovalent counterion, (b) -PO(O⁻)₂.2M⁺, (c) -PO(O⁻)₂.D² +,wherein D²⁺ is a pharmaceutically acceptable divalent counterion, (d)-CH(R⁴)-PO(OH)O-⁻. M⁺, wherein R⁴ is hydrogen or C₁₋₃ alkyl, (e)-CH(R⁴)-PO(O⁻)₂.2M⁺, (f) -CH(R⁴)-PO(O⁻)₂.D²⁺, (g) -SO₃ -.M⁺, (h)-CH(R⁴)-SO₃ -.M³⁰ , (i) -CO-CH₂ CH₂ -CO₂ -.M⁺, (j)-CH(CH₃)-O-CO-R⁵,wherein R⁵ is selected from the group consisting of: ##STR13## (k)hydrogen, with the proviso that is p is 0 and none of R¹¹, R¹² or R¹³are -OX, then X is other than hydrogen;Y is selected from the groupconsisting of: (1) a single bond, (2) -O-, (3) -S-, (4) -CO-, (5) -CH₂-, (6) -CHR¹⁵ -, and. (7) -CR¹⁵ R¹⁶ -, wherein R¹⁵ and R¹⁶ areindependently selected from the group consisting of:(a) C₁₋₆ alkyl,unsubstituted or substituted with one or more of the substituentsselected from:(i) hydroxy, (ii) OXO, (iii) C₁₋₆ alkoxy, (iv) phenyl-C₁₋₃ alkoxy, (v) phenyl, (vi) -CN, (vii) halo, (viii) -NR⁹ R¹⁰, whereinR⁹ and R¹⁰ are as defined above, (ix) -NR⁹ COR¹⁰, wherein R⁹ and R¹⁰ areas defined above, (x) -NR⁹ CO₂ R¹⁰, wherein R⁹ and R¹⁰ are as definedabove, (xi) -CONR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above, (xii)-COR⁹, wherein R⁹ is as defined above, and (xiii) -CO₂ R⁹, wherein R⁹ isas defined above; (b) phenyl, unsubstituted or substituted with one ormore of the substituent(s) selected from:(i) hydroxy, (ii) C₁₋₆ alkoxy,(iii) C₁₋₆ alkyl, (iv) C₂₋₅ alkenyl, (v) halo, (vi) -CN, (vii) -NO₂,(viii) -CF₃, (ix) -(CH₂)_(m) -NR⁹ R¹⁰, wherein m, R⁹ and R¹⁰ are asdefined above, (x) -NR⁹ COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,(xi) -NR⁹ CO₂ R¹⁰, wherein R⁹ and R¹⁰ are as defined above, (xii) -CONR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above, (xiii) -CO₂ NR⁹ R¹⁰,wherein R⁹ and R¹⁰ are as defined above, (xiv) -COR⁹, wherein R⁹ is asdefined above, and (xv) -CO₂ R⁹, wherein R⁹ is as defined above;Z isselected from: (1) hydrogen,(2) C₁₋₆ alkyl, and(3) hydroxy, with theproviso that if Y is -O-, Z is other than hydroxy, or if Y is -CHR¹⁵ -,then Z and R¹⁵ are optionally joined together to form a double bond. 2.The method of claim 1 wherein the compound of formula I:R² and R³ areindependently selected from the group consisting of:(1) hydrogen, (2)C₁₋₆ alkyl, (3) C₂₋₆ alkenyl, and (4) phenyl; R⁶, R⁷ and R⁸ areindependently selected from the group consisting of:(1) hydrogen, (2)C₁₋₆ alkyl, (3) fluoro, (4) chloro, (5) bromo, (6) iodo, and (7) -CF₃ ;R¹¹, R¹² and R¹³ are independently selected from the group consistingof:(1) fluoro, (2) chloro, (3) bromo, and (4) iodo; A is unsubstitutedC₁₋₆ alkyl; B is selected from the group consisting of: ##STR14## p is0; X is selected from:(a) -PO(OH)O⁻.M⁺, wherein M⁺ is a pharmaceuticallyacceptable monovalent counterion. (b) -PO(O⁻)₂.2M⁺, (c) -PO(O⁻)₂.D²⁺,wherein D²⁺ is a pharmaceutically acceptable divalent counterion, (d)-CH(R⁴)-PO(OH)O⁻.M⁺, wherein R⁴ is hydrogen or methyl, (e)-CH(R⁴)-PO(O⁻)₂.2M⁺, wherein R⁴ is hydrogen or methyl, (f)-CH(R⁴)-PO(O⁻)₂.D²⁺, wherein R⁴ is hydrogen or methyl, (i) -CO-CH₂ CH₂-CO₂ ⁻.M⁺, (j) -CH(CH₃)-O-CO-R⁵, wherein R⁵ is selected from the groupconsisting of: ##STR15## Y is -O-; Z is hydrogen or C₁₋₄ alkyl.
 3. Themethod of claim 1 wherein the compound of formula I:Z is C₁₋₄ alkyl. 4.The method of claim 1 wherein the compound of formula I:Z is -CH₃. 5.The method of claim 1 wherein the compound of formula I:A is -CH₂ - or-CH(CH₃)-.
 6. The method of claim 1 wherein the compound of formula I:-Bis selected from the group consisting of: ##STR16##
 7. The method ofclaim 1 wherein the compound of formula I:-A-B is selected from thegroup consisting of: ##STR17##
 8. The method of claim 1 wherein thecompound of formula I:-A-B is selected from the group consisting of:##STR18##
 9. The method of claim 1 wherein the compound of formula I:Xis selected from the group consisting of: (a) -PO(O⁻)₂.2M⁺, wherein M⁺is a pharmaceutically acceptable monovalent counterion, (b)-PO(O⁻)₂.2D²⁺, wherein D²⁺ is a pharmaceutically acceptable monovalentcounterion, (c) -CH(CH₃)-O-CO-CH₂ CH₂ -NH₃ ⁺. M⁻, and (d)-CH(CH₃)-O-CO-CH₂ CH₂ -NH₂ ⁺ -(CH₂ CH₂ -OH).M⁻.
 10. The method of claim1 wherein the compound of formula I is of the structural formula II:##STR19## or a pharmaceutically acceptable salt thereof, wherein R², R³,R⁶, R⁷, R⁸, R¹¹, R¹², R¹³, A, B and Z are as defined in claim
 1. 11. Themethod of claim 1 wherein the compound of formula I is of the structuralformula III: ##STR20## or a pharmaceutically acceptable salt thereof,wherein R², R³, R⁶, R⁷, R⁸, R¹¹, R¹², R¹³, A, B and Z are as defined inclaim
 1. 12. A method for the treatment or prevention of emesis in amammal in need thereof which comprises the administration to the mammalof an effective amount of a compound which is selected from the groupconsisting of:(1)2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)-methyl)morpholineN-oxide; (2)2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-4-(3-(4-(ethoxycarbonyloxy-1-ethyl)5-oxo-1H-1,2,4-triazolo)-methyl)morpholine; (3)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro))-phenyl-4-(3-(4-monophosphoryl-5-oxo-1 H-1,2,4-triazolo)-methyl)morpholine; (4)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(1-monophosphoryl-5-oxo-1H-1,2,4-triazolo)-methyl)morpholine; (5)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(2-monophosphoryl-5-oxo-1H-1,2,4-triazolo) methyl) morpholine; (6)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(5-oxyphosphoryl-1H-1,2,4-triazolo)-methyl morpholine;(7)2-(S)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(1-phosphoryl-5-oxo-4H-1,2,4-triazolo)-methyl)morpholine;ora pharmaceutically acceptable salt thereof.
 13. The method of claim 12wherein the compound is present as the bis(N-methyl-D-glucamine) salt.14. A method for the treatment or prevention of emesis in a mammal inneed thereof which comprises the administration to the mammal of aneffective amount of a compound which is selected from the groupconsisting of: ##STR21## wherein K⁺ is a pharmaceutically acceptablecounterion.
 15. The method of claim 14 wherein the compound K⁺ isN-methyl-D-glucamine.